RxPG News : Colon

Alcohol, cigarettes can cause bowel cancer

Mon, 22 Jun 2009 11:11:40 PST

( from http://www.rxpgnews.com ) Beware of alcohol and cigarettes, they can cause bowel cancer, says a new study.

A new global study has shown that people who consume large quantities of alcohol - have a 60 percent greater risk of developing the cancer, compared to others.

Rachel Huxley, professor at The George Institute, who led the study, said the most startling finding was 'the strong, and largely, unknown association between high intakes of alcoholic beverages with risk of colorectal - cancer.'

'Most people probably know that being overweight and having poor dietary habits are risk factors for the disease, but most are probably unaware that other lifestyle risk factors such as alcohol consumption, cigarette smoking and diabetes are also important culprits,' she added.

Smoking, obesity and diabetes were also associated with a 20 percent greater risk of

developing bowel cancer - the same risk linked with consuming high intake of red and

processed meat.

One million new cases of bowel cancer are diagnosed worldwide every year. The disease claims more than half of them.

According to a George Institute release, Australia's National Health and Medical Research Council recommends individuals shouldn't be drinking more than two standard drinks per day,

On a positive note, researchers also demonstrated that physical activity lowered an individual's risk of the disease but surprisingly, there was little evidence to indicate that high intakes of fruit and vegetables protected from bowel cancer.

TSPAN1 expression-a useful tool to evaluate prognosis in colorectal cancer

Sun, 24 May 2009 10:38:06 PST

( from http://www.rxpgnews.com ) The colorectal cancer is thought to be resulted from a combination of environmental factors, diet, lifestyle, chronic inflammation and accumulation of specific genetic alterations. The pathogenesis and development of colorectal cancer involve multi-genes and multi-steps. TSPAN1 (GenBank Accession No. AF065388) is a new member of TM4SF located at chromosome 1 p34.1. It encodes a 241 amino acid protein. TSPAN1 was reported as a tumor-related gene recently.

A research team led by Dr Jian-Wei Zhu from Nantong University, China, investigated the association between TSPAN1 and human colorectal adenocarcinoma. Their study will be published on May 14, 2009 in the World Journal of Gastroenterology

In this study, total RNA was extracted in 20 human adenocarcinoma tissues for TSPAN1 mRNA assay by RT-PCR. Eighty-eight specimens of human colorectal adenocarcinoma were surgically removed. TSPAN1 protein levels in cancer tissues were determined by immunohistochemistry using a polyclonal antibody against self-prepared TSPAN1. The correlation between TSPAN1 expression and the clinicopathological factors and the overall survival rate was analyzed by univariate and multivariate assay.

By RT-PCR assay, it was shown that TSPAN1 mRNA was detected in 90.0% (18/20) of cancerous tissue. The light density of TSPAN1 mRNA expression levels was 0.89 ±0.30 in adenocarcinoma by gel-image system. TSPAN1 protein expression was detected in 78.41 %( 69/88) and weakly expressed in 40% normal colorectal tissues by immunohistochemistry. There were significant differences between colorectal adenocarcinoma and normal control epithelium (P < 0.05). TSPAN1 protein expression in colorectal cancerous tissue was significantly correlated with the histological grade, cell expression PCNA, lymph nodal metastasis and TNM staging of the disease. Patients with TSPAN1 protein over expression had a significantly shorter survival period than that in patients with TSPAN1 protein negative or weak expression, respectively (P<0.05). Furthermore, by multivariate analysis TSPAN1 protein expression demonstrated an independent prognostic factor for human colorectal cancers (P<0.05, relative risk 0.755; 95% confidence interval 0.302-1.208).

The result indicated that testing TSPAN1 expression in tissues would be a useful tool to evaluate the prognosis of patients with colorectal cancer

Advances in screening and markers improve early detection of colorectal cancer

Wed, 23 May 2007 15:59:37 PST

( from http://www.rxpgnews.com ) Although colorectal cancer is the second leading cause of cancer death in the United States, when detected early, it has one of the highest cure rates. For this reason, innovative and improved methods to screen for and detect this disease are essential. Research presented today at Digestive Disease Week? 2007 (DDW?) demonstrates the breadth of technological and research advances that are helping to decrease both the number of deaths and the number of new cases of colorectal cancer diagnosed in the United States. DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

Rice bran can reduce the risk of intestinal cancer

Tue, 27 Mar 2007 00:57:59 PST

( from http://www.rxpgnews.com ) A study by biomedical scientists at the University of Leicester has revealed for the first time that rice bran could reduce the risk of intestinal cancer.

The research in the University's Department of Cancer Studies and Molecular Medicine has not been tested on humans, but research in the laboratory has produced promising results.

The research has been published in the British Journal of Cancer.

The results of a controlled laboratory study in a preclinical model of gastrointestinal adenoma demonstrated that consumption of a high daily dose of stabilized rice bran caused an average 51% reduction in the number of precancerous adenomas in the intestinal tract.

Professor Andreas Gescher of the University of Leicester in the UK, the principal investigator, said:

"We compared the cancer-preventive efficacy of rice bran with respect to prostate, breast and intestinal cancers. Whilst there was no effect of rice bran on the development of prostate or breast cancer, rice bran significantly retarded the development of intestinal adenomas. The effect was dependent on the fibre content of the bran. The dose we used translates into approximately 200g rice bran per day in humans. We believe a promising area of future research would be to study the potential colorectal cancer-preventing properties of stabilized rice bran.

"It is known that bran from wheat and rye have anti-cancer properties but this is the first time that this has been shown for rice bran. It appears that rice bran may have a role to play in reducing the development of adenomas, which can be a pre-cursor to cancer. No one has compared the efficacy of the different brans, such as rice, wheat, rye or oat and this may be an interesting future direction for researchers."

Simutaneous removal of primary and liver metastasis favourable in some colorectal cancer patients

Sun, 18 Mar 2007 14:16:16 PST

( from http://www.rxpgnews.com ) A single surgery to remove cancer from both the colon and the liver to which it has spread may be better in some cases than the current standard treatment of two separate surgeries with chemotherapy in between, according to a study led by Duke University Medical Center researchers.

Simultaneous surgeries on the colon and liver may reduce the length of a patient's stay in the hospital and potentially lessen the risk of surgical complications without compromising long-term survival, according to the study.

"In about a third of patients who are newly diagnosed with colorectal cancer, the cancer has already spread to the liver," said Bryan Clary, M.D., a surgical oncologist at Duke and senior investigator on the study. "The standard approach for these patients has been to remove the colorectal cancer and give them chemotherapy afterwards, waiting to remove liver tumors later if patients do not appear to be developing disease elsewhere in the body. These findings suggest there might be an alternative that is as safe and may even lead to better outcomes."

Colorectal cancer is the third most common cancer in both men and women in the United States, and it is the second-leading cause of cancer-related deaths in this country.

The researchers presented their findings on Saturday, March 17, in a plenary session at the annual meeting of the Society of Surgical Oncology in Washington, D.C. The study was funded by the National Institutes of Health and Duke's Department of Surgery.

The researchers looked at outcomes for 610 patients who had undergone either simultaneous or separate surgeries for removal of colorectal cancer from the colon or rectum and from the liver, where it had spread. The patients were treated at three academic medical centers -- Duke, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University and the University of Texas M.D. Anderson Cancer Center -- between 1985 and 2006.

"We looked at factors including surgical complications and survival data among the groups and found that in certain patient groups, simultaneous surgery was as safe as separate surgeries, could shorten the length of hospital stay and might lead to fewer surgery-related complications," said Srinevas Reddy, M.D., a general surgery resident at Duke and the study's lead author.

Chemotherapy is used in addition to cancer surgery to kill cancer cells that may reside undetected in other parts of the body. Patients having separate surgeries commonly receive chemotherapy both after their initial colon surgery and then again after their liver surgery, Clary said. But the powerful drugs used in chemotherapy can have a toxic effect on other organs, including the liver, that may increase the risk of liver surgery, he said.

The researchers also discovered that chemotherapy administered after surgical removal of cancerous liver segments favorably affected survival rates, whether or not that surgery was done alone or in conjunction with colorectal surgery. Chemotherapy administered before liver surgery showed no benefits, Clary said.

The researchers found that simultaneous surgery was only as safe as standard treatment among patients who required a minimal amount of liver to be removed. But for those whose cancer was more extensive requiring larger amounts of liver to be removed, separate surgeries remain the better treatment choice.

"For patients who require a great deal of liver to be removed, the complication risks associated with such extensive surgery outweigh the benefits of doing it all at once," Clary said.

About half of patients with colorectal and liver tumors could be eligible for the simultaneous surgery, which could translate to about 25,000 patients per year, he said.

"This study is important because it shows that patients with liver metastases at the time of their original colorectal cancer diagnosis might benefit from evaluation at a multidisciplinary center that includes not only medical oncologists and surgical oncologists skilled in colorectal surgery, but also surgeons capable of performing liver surgery," Clary said.

Follow-up endoscopic surveillance in colorectal cancer patients improves survival

Thu, 15 Mar 2007 08:39:06 PST

( from http://www.rxpgnews.com ) Colorectal cancer patients who undergo colonoscopic surveillance during follow-up after surgery experience improved survival, according to a study to be published in the April issue of Clinical Gastroenterology and Hepatology but currently available on-line. Results of the study suggest that colorectal cancer patients should undergo routine colonoscopic surveillance at one year after their surgery and that more intensive surveillance may be needed in patients found to have advanced neoplasia as well as those with a prior history of adenomatous colon polyps.

"The results of our study provide additional evidence that colorectal cancer survivors benefit from surveillance with colonoscopy, and it appears that the initial surveillance colonoscopy should be performed at one year after colon resection because of the significant risk of additional cancers and polyps in these patients," according to Stephen J. Rulyak, MD, MPH, lead author of the study and Acting Assistant Professor in the Division of Gastroenterology at the University of Washington in Seattle.

The study included a total of 1,002 patients identified from the Group Health Cooperative, a large health system in Washington State, and consisted of equal proportions of men and women, the majority of whom were aged 60 years or older. More than 700 (70 percent) were alive at the end of the study period and the cumulative survival for the study group was 96 percent at one year and 68 percent at five years.

Patients who underwent one or more colon examinations during follow-up had improved survival compared with patients who did not undergo examination (652 patients versus 350 patients). Patients estimated five-year survival was similar regardless of whether the initial follow-up colon exam was performed within 18 months of diagnosis (78.0 percent), between 18 and 35 months of diagnosis (75.5 percent) or between 36 and 60 months of diagnosis (77.3 percent). However, among patients who did not undergo a colon examination during follow-up, the five-year survival was at least 45 percent lower (52.5 percent).

Twenty patients in the study (3.1 percent) were diagnosed with a second colorectal cancer, including nine cancers detected within 18 months of initial cancer diagnosis. Advanced neoplastic polyps were also more common (15.5 percent) when the initial colonoscopy was delayed until 36 to 60 months after diagnosis compared with patients who had an initial colonoscopy within 18 months (6.9 percent). Patients with a prior history of adenomas were more likely to have advanced neoplastic polyps on follow-up. In addition, patients with advanced neoplastic polyps on the initial surveillance colonoscopy were frequently found to have advanced neoplasia on subsequent colonsocopies (81 percent).

"The best prevention we have against colorectal cancer is screening. All individuals over the age of 50 or those with a family history of the disease should be screened for this deadly disease," according to Charles Mel Wilcox, MD, Editor-in-Chief, Clinical Gastroenterology and Hepatology, and professor of medicine, University of Alabama, Birmingham. "This study provides further proof of the value of screenings and the lives that can be extended and saved."

Colorectal cancer is the third leading cause of cancer-related deaths and affects men and women equally. An estimated 112,340 new cases of colon cancer and an estimated 41,420 cases of rectal cancer will be diagnosed this year, according to the National Cancer Institute. More than 52,000 Americans will die from colorectal cancer in 2007. Colorectal cancer rates have been decreasing steadily over the past several decades due to an increase in awareness and screening.

Researchers identify cell pathway which plays a critical role in the development of colon cancer

Tue, 20 Feb 2007 07:09:09 PST

( from http://www.rxpgnews.com )

Most cancers begin as polyps%uE8B7 growth of tissue into the center of the colon or rectum and when typed as adenoma, can become cancerous. The mortality rates have been declining, this in part due to earlier screenings, awareness of symptoms, removing polyps and improved treatments through advances in research discoveries.

For the one in 18 men and women who will be diagnosed with cancer of the colon and rectum during their lifetime and over 150,000 people diagnosed on a yearly basis, todays genetic research news offers some optimism.

In a study to be published in the Proceedings of the National Academy of Sciences, {PNAS Online Edition Feb. 20-23, 2007} led by Zhenghe John Wang, Ph.D., Assistant Professor, Department of Genetics at Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, researchers have identified a cell pathway which plays a critical role in the development of colon cancer. This pathway may also play a role in the development of lung and stomach cancers.

Investigators say they have identified STAT3 {signal transducer and activator of transcription 3}, as a target regulated by PTPRT {Receptor Protein tyrosine phosphatase T}, which was previously identified to be mutated in colon, lung and stomach cancer patients.

"The role of protein tyrosine phosphatase in cancer is still an under-explored area. Our study shows that receptor protein tyrosine phosphatase T regulates an important signaling pathway that is critical in cancer development. This identification will allow new approaches to pharmacological designs and facilitate alternative approaches for cancer treatment? said Wang.

With over 52,000 deaths each year, colon and rectal cancer is the second leading cause of cancer death in the United States. Colon and rectal cancers begin in the digestive system and may start in a variety of different areas of the GI tract which take years to progress. Both colon and rectal cancer have many commonalities and for that are commonly referred as colorectal cancer? Most cancers begin as polypsa growth of tissue into the center of the colon or rectum and when typed as adenoma? can become cancerous. The mortality rates have been declining, this in part due to earlier screenings, awareness of symptoms, removing polyps and improved treatments through advances in research discoveries.

The finding that STAT3 is important for the growth of colon cancer is highly novel, and provides new impetus to the development of drugs that will target this molecule? said Dr. Sanford Markowitz, Ingalls Professor of Cancer Genetics at Case Western Reserve University School of Medicine and Investigator in The Howard Hughes Medical Institute, Case Medical Center.

The study also included collaboration with Bert Vogelstein, Victor Velculescu and Kenneth Kinzler of The Johns Hopkins Kimmel Cancer Center and a team led by Roberto Polakiewicz at Cell Signaling Technology Incorporation.

Regular aerobics protects men from colon cancer

Wed, 13 Sep 2006 20:03:37 PST

( from http://www.rxpgnews.com ) Regular, moderate-to-vigorous aerobic exercise significantly reduces a risk factor associated with the formation of colon polyps and colon cancer in men, according to a study led by researchers at Fred Hutchinson Cancer Research Center. The findings, from the first randomized clinical trial to test the effect of exercise on colon-cancer biomarkers in colon tissue, appear in the September issue of Cancer Epidemiology, Biomarkers and Prevention.

"In men who met the study's exercise prescription of an hour of aerobic activity per day, six days a week for a year, we saw a substantial decrease in the amount of cellular proliferation in the areas of the colon that are most vulnerable to colon cancer," said lead author Anne McTiernan, M.D., Ph.D., an internist and epidemiologist who directs the Hutchinson Center's Prevention Center. "However, we found that even four hours or more of exercise weekly was enough to produce a significant benefit," she said.

Specifically, the researchers saw a decrease in the number of actively dividing cells, or cellular proliferation, within the colonic crypts tiny tube-like indentations in the lining of the colon, or epithelium, which help regulate the absorption of water and nutrients. "A certain amount of cellular proliferation at the bottom part of the crypt is normal. But when these cells start dividing too quickly, they can migrate up the sides of the crypt to the surface and eventually form a polyp," she said. While most polyps are benign, over time some types can become malignant.

The researchers found an inverse relationship between the amount and intensity of exercise and the levels of cellular proliferation, as measured by how far the migrating cells traveled from the base of the crypt and up the sides toward the surface of the epithelium.

A significant decline in cellular proliferation was observed among men who worked out an average of four hours a week or more and in those whose cardiopulmonary fitness was most robust. The greatest decrease in cellular proliferation was seen in men who exercised more than five hours a week. No such decrease was seen among sedentary men or those who exercised infrequently.

"Proliferation in the upper section of the colon crypt decreased among those exercising for a mean 250 minutes per week or greater, which is important because this pattern of proliferation is most associated with risk for colon cancer," the researchers reported.

Body weight did not appear to have an impact on the effect of exercise on cellular proliferation. "These effects were independent of weight. Vigorous exercise was helpful for men of any size, as long as they worked out nearly every day," said McTiernan, a member of the Public Health Sciences Division at the Hutchinson Center and a faculty member at the University of Washington.

So while men of all shapes and sizes seemed to benefit from frequent, vigorous workouts of at least four hours a week, the investigators saw no notable changes in markers of cellular proliferation in their female counterparts. "This finding supports previous epidemiological studies that also have suggested that regular exercise reduces the risk of colon cancer in men more than in women," McTiernan said. "It's not a finding that we really wanted to see, but at least our results are consistent with those of previous population-based, epidemiological studies."

The mechanism behind the null effect in female exercisers is unknown. Possible explanations, the researchers hypothesize, include the fact that exercise lowers the level of naturally occurring estrogen, a hormone that protects the colon. Another possible explanation is that the men worked out more vigorously and more often than did the women. "On average, the men in the study met their physical-activity goal of an hour a day, six days a week, whereas the women met about 80 percent of their goal. Also, the men spent more time jogging or running compared to the women," McTiernan said. "The women still did very well in this exercise intervention, but it may not have been enough to protect the colon."

The study, which was funded by the National Cancer Institute and the National Institutes of Health, involved 202 healthy, sedentary Seattle-area men and women between the ages of 40 and 75. All had undergone a colonoscopy within three years of participating in the year-long intervention to confirm the absence of colon cancer. Before and after completion of the study, the participants also underwent a flexible sigmoidoscopy, a procedure that allows for visual inspection of the rectum and lower colon, and the collection of tissue samples from the mucosal lining of the colon.

Half of the participants were randomly assigned to an exercise group and half were randomly assigned to a comparison, or control group. The exercisers were asked to engage in moderate to vigorous activity six days a week for a year, both on their own and at a one of several exercise facilities (including one located at the Hutchinson Center). They were also asked to maintain their regular eating habits for the duration of the study. Those in the control group were asked to maintain their current activity level and diet for a year, after which they had an opportunity to exercise for two months at no cost with a personal trainer at one of several study facilities. The Seattle Foundation and Precor Inc. of Bothell donated exercise equipment for the state-of-the-art Hutchinson Center exercise facility.

Adherence to the program was excellent, as indicated by daily exercise logs; 80 percent of the exercisers met more than 80 percent of their six-hour-a-week goal.

A major strength of the study was its randomized, controlled, clinical-trial design, which enabled the researchers to minimize the impact of confounding factors, document exercise activity and examine the direct effects of exercise on colon tissue.

"I think that this study really underscores the new activity recommendations from the USDA and the Institute of Medicine, both of which advise people to exercise an hour a day, six days a week for weight control and general health," McTiernan said.

Researchers from the University of Washington School of Medicine, Veterans Affairs Puget Sound Health Care System and Virginia Mason Medical Center in Seattle collaborated on the study.

Role for MicroRNAs in Oxygenation, Nourishing of Colon Tumors

Tue, 01 Aug 2006 14:45:37 PST

( from http://www.rxpgnews.com ) Researchers from the University of Pennsylvania School of Veterinary Medicine have identified how molecules of microRNA are responsible for the growth of blood vessels in a model for human colon cancer. The process, called angiogenesis, results in ability of ravenous cancer cells to recruit blood vessels and receive a steady supply of nutrients and oxygen.

The findings, which appear in the online version of Nature Genetics, suggest that these microRNAs might also be a good target for future therapeutics designed to slow the growth of cancer cells.

"These findings also uncover a new role for a well-known cancer-causing gene called MYC," said Andrei Thomas-Tikhonenko, professor in Penn Vet's Department of Pathobiology. "We have discovered that, within a tumor cell, one of the tasks of MYC is to turn loose a particular set of microRNAs, which then becomes responsible for promoting the growth of new blood vessels that nourish the tumor."

MicroRNAs are, as the name implies, short strands of RNA. During the last few years, microRNAs have been found to have a significant role in the process by which genes are translated into proteins. Clusters of microRNA have been caught associated with messenger RNA, the intermediary molecule that "instructs" the cell's protein-building machinery. In particular, microRNAs help determine the life-span of messenger RNA and, therefore, how many copies of a protein can be made from a single messenger RNA molecule.

The Penn researchers discovered the role of microRNAs in angiogenesis while studying what makes MYC unique among other cancer-causing genes, or oncogenes. In particular, they were curious why cells with hyperactive MYC dont accumulate particularly fast in Petri dishes yet grow explosively in animal models for the disease

"There are obviously no blood vessels in a Petri dish, so the angiogenic properties of the MYC gene are not advantageous," said Michael Dews, senior researcher in the Thomas-Tikhonenko lab. "In the incubator, the cancer cells grow at normal rates, but in the mouse model you see them recruiting a lot of blood vessels and really taking off. Curiously, this is not the case with some other oncogenes. So, what makes MYC special?"

The MYC protein is known to have a role in determining how certain genes are transcribed into messenger RNAs. To understand the role of MYC in angiogenesis, the Penn researchers used microarray technology to screen MYC-positive and MYC-negative cancerous cells for the presence or absence of 192 known pro- and anti-angiogenesis molecules. They found that, while MYC did not lead to excessive amounts of pro-angiogenesis molecules, it did seem to depopulate an entire family of anti-angiogenesis molecules related to the so-called thrombospondin-1 protein. MYC effectively disabled the brakes that slow angiogenesis.

The Thomas-Tikhonenko lab had previously demonstrated that MYC decreases the lifespan of the messenger RNA encoding thrombospondin. Since microRNAs had emerged as important regulators of messenger RNA stability, the Penn researchers believed there was a good chance of a MYC-microRNA-thrombospondin connection.

Their long-standing collaborator Chi Dang, a professor at Johns Hopkins University, suggested talking to another Hopkins researcher, Joshua Mendell. Mendell had extensive expertise in microRNA function and just a few months ago teamed up with Dang to identify MYC as an important regulator of microRNAs. The new collaboration between the Thomas-Tikhonenko and Mendell laboratories identified a missing link between MYC and thrombospondin, which indeed turned out to be a microRNA cluster designated miR-17-92. In the key experiment the researchers engineered poorly angiogenic tumor cells to produce copious amounts of miR-17-92. These modified cells, just like cells with hyperactive MYC from earlier experiments, formed much larger tumors with better blood supplies.

"It has become increasingly clear that microRNAs are abnormally expressed in many types of cancer and select microRNAs have been demonstrated to act as a new type of oncogene," Mendell said. "As such, microRNAs represent an entirely new class of potential targets for cancer therapy."

According to Mendell, an "anti-sense" version of miR-17-92 could bind to miR-17-92, thereby canceling its effects. If it is possible to deliver regular miR-17-92 to increase angiogenesis, as was demonstrated in the Nature Genetics paper, it may be possible to deliver anti-sense miR-17-92 to decrease angiogenesis and tumor growth.

New genetic test to spotlight heightened bowel cancer risk

Mon, 10 Jul 2006 20:17:37 PST

( from http://www.rxpgnews.com ) Cancer Research UK scientists have devised a new means to identify groups of people genetically more at risk from bowel cancer. This could lead to new measures to prevent the disease for thousands of people in the future, according to a study published in the New England Journal of Medicine (Wednesday 28 June 2006).

A team at the University of Edinburgh undertook the largest ever study of a particular class of genes MLH1, MSH2 and MSH6, which when faulty are linked to a minority of all bowel cancers, and devised a new genetic screening method to assess if patients had faults in these genes. Conventional testing of every single patient with bowel cancer would be extremely expensive and not totally accurate.

The current methods of identifying patients with these genetic faults are complex, so the researchers devised a more effective way of detecting them. They tested 870 patients and found 38 of them, or four per cent, had these faults. These genetic errors means that those patients have a higher risk of bowel and some other cancers, and a figure of four per cent is higher that previously reported estimates.

34,900 bowel cancer cases diagnosed in the UK each year and many occur in someone with a family history of the disease. Identifying groups of patients with genetic faults could improve their treatment and survival. However, the discovery will also prove useful for family members who may have inherited these genetic defects they could, in the future, be monitored to ensure the disease is detected early before symptoms arise.

The large-scale study has been running across Scotland for seven years and has recruited the majority of patients who have developed bowel cancer under the age of 55 years, soon after diagnosis. Over 1300 patients have so far been recruited. Without taking into account prior knowledge of their family history, the researchers studied the patients clinical data and took blood and tumour samples to assess them for faults in three of their DNA repair proteins. This approach also allowed the research team to analyse the cancer survival statistics of patients carrying the defective genes and the results emphasise the importance of early detection and prevention.

DNA repair proteins fix damaged strands of DNA, helping to keep the bodys cells under control. However, when damaged DNA cant be repaired, mutations can occur, causing cells to replicate uncontrollably, and this is a major characteristic of cancer.

Lead researcher Professor Malcolm Dunlop, from the Colon Cancer Genetics Group of University of Edinburgh and the Medical Research Council Human Genetics Unit, said: This large study has allowed us to develop a new means to identify patient groups who are likely to carry genetic defects responsible for their bowel cancer. The model we developed is easily accessed on our website for clinicians who can then use the prediction to determine who needs genetic blood tests. Our method also shows that a higher proportion of bowel cancer patients fulfilled the criteria for having genetic faults than the current methods would suggest.

This discovery encouraged the researchers to test their theory on a separate smaller number of patients who were diagnosed at a younger age. This group would further suggest a genetic cause because cancer typically affects older people as theyve had more time to accumulate genetic damage. A higher number of cases with the faulty genes in the younger group would clearly point to an inherited risk and thats what was found. Also, the researchers found that twice as many men as women carried the faults, an intriguing finding that is possibly due to the hormonal differences between the sexes, lifestyle differences or perhaps differences in X and Y chromosomes.

Professor Dunlop added: In the long term, we hope this study will help identify all bowel cancer patients who carry one of these gene faults and then offer tests to their relatives who have not yet developed cancer, so that preventative measures can be put in place. The findings will also help determine the best treatment for patients with gene faults.

Professor Timothy O'Shea, University of Edinburgh principle, said: "This research has identified a very useful method that could in future help doctors to rapidly assess whether a newly diagnosed bowel cancer patient carries these genetic faults. Given the significant number of bowel cancer cases in the UK each year, any information which might highlight patients requiring slightly different treatment to prevent their disease from returning is to be welcomed."

Professor Alex Markham, chief executive of Cancer Research UK, said: These are very valuable findings that will help scientists better understand the process of bowel cancer development, particularly in people who are diagnosed at a young age.

"Identifying people who would benefit from regular examination of the bowel, a colonoscopy, is extremely important - we know that this can prevent the majority of bowel cancers in people who are genetically prone to the disease from developing, because pre-cancerous growths can be detected and removed before they progress to cancer."

$2.6 million in grants for metastatic colon cancer research

Sat, 08 Jul 2006 21:58:37 PST

( from http://www.rxpgnews.com ) The American Association for Cancer Research announces the first 11 recipients of the new Jeannik M. Littlefield-AACR Grants in Metastatic Colon Cancer Research. The awards, ranging to $250,000, were established in February 2006, to support innovative research projects designed to accelerate the discovery and development of new agents to treat metastatic colon cancer. Grant awards were selected through a rigorous and highly competitive process by a committee of accomplished senior scientists. AACR is currently distributing a total of $2,644,977 to the successful investigators.

"Among the 114 applications submitted, these 11 awardees were judged to have the most merit," said David Irwin, Ph.D., managing director of the Science and Education Division of the AACR. "We offer our sincere congratulations to the investigators, and anticipate they will make substantial contributions to this field of cancer research."

The Jeannik M. Littlefield-AACR Grants in Metastatic Colon Cancer Research are sponsored by Jacques and Sandy Littlefield of Portolo Valley, California, who donated $3 million to the AACR in late 2005. They are named for Mr. Littlefield's mother.

Recipients of the 2006 Jeannik M. Littlefield-AACR Grants in Metastatic Colon Cancer Research are:

Peter Carmeliet, M.D., Ph.D., Flanders Interuniversity Institute for Biotechnology, "Preclinical Development of anti-P1GF Antibodies for Metastatic Colon Cancer." In the quest to block angiogenesis, this study will test a homologue of VEGF P1GF. Antibodies to P1GF will be used in cell lines and xenograft models. The approach has strong potential for clinical application because blocking P1GF should not interfere with normal angiogenesis.

Steven A. Curley, M.D., University of Texas M.D. Anderson Cancer Center, "Carbon Nanotubules and Gold Nanoparticles as Radiofrequency Targets." The goals are to couple antibodies to nanotubules and gold particles to affect specific homing to metastases. Inoperable metastases can then be thermally ablated using microwaves.

Wafik El-Deiry, M.D., Ph.D., University of Pennsylvania, "Novel Therapy for Resistant Metastatic Colon Cancer." The goals are to define the mechanisms in colon cancer that make tumor cells resistant to apoptosis, and develop combination drug therapies that can reverse the apoptotic defect.

Edgar G. Engelman, M.D., Stanford University, "T-Cell Signaling in Metastatic Colon Cancer." This study will examine the failure of the immune system to detect colon cancer cells with the goal of identifying and profiling tumor-associated signaling abnormalities in T-cells. This will affect choice of therapy and will show whether signalling abnormalities can be reversed using immunotherapy.

Douglas V. Faller, M.D., Ph.D., Boston University School of Medicine, "PKC-Delta as a Therapeutic Target in Colon Cancer." The approach is to inhibit PKC-delta which is not critical for normal cellular growth but which, in tumor cells, inhibits Ras-mediated apoptosis. Molecular strategies will identify more active and more specific inducers of the Ras-mediated apoptotic pathway.

Robert D. Ladner, Ph.D., University of Southern California, "Histone Deacetylase Inhibitors for the Treatment of Metastatic Colon Cancer." New approaches will be developed to enhance the effectiveness of 5FU using histone de-acetylase inhibitors.

Eric Lagasse, Ph.D., PharmD, University of Pittsburgh, "Metastatic Colon Cancer, Stem Cells and Bioreactors." Using an artificial bioreactor that models the environment in liver and colon cancer, stem cells will be identified and expanded in vitro. Therapy will then be refined and customized preclinically before being administered to patients.

Nouri Neamati, Ph.D., University of Southern California, "Preclinical Development of SC144 in Metastatic Colon Cancer." A new agent, SC144 has been shown to cause up-regulation of IL24 - a very potent anticancer protein. SC144 will be fully evaluated in mouse models and then, potentially, trials will be extended to humans.

Boris C. Pasche, M.D., Ph.D., Northwestern University, "Targeting the TGFBR1*6A in Metastatic Colon Cancer." This study will use antibodies to TGFB and assess their effects on colon tumor growth in mice. A humanized antibody will be used in a Phase I/II clinical trial.

Gary K. Schwartz, M.D., Memorial Sloan Kettering Cancer Center, "Targeting the Notch Signaling Pathway in Metastatic Colon Cancer." The effectiveness of combining notch and ras inhibitors such as gamma secretase inhibitors will be examined in colon cancer cells as a prerequisite to designing a Phase I clinical trial.

Oliver Stoeltzing, M.D., Universitaet Regensburg, "The Role of Hsp 90 in Hepatic Growth of Colorectal Cancer Metastases." Using colon cell lines and xenografts, this study will examine the role of tissue hypoxia in colorectal hepatic metastases and the suitability of targeting Hsp 90 for molecular targeted therapies.

NSAIDs don't reduce colorectal cancer risk in chronic smokers

Sat, 01 Jul 2006 17:28:37 PST

( from http://www.rxpgnews.com ) It is widely known that the use of aspirin and other nonsteroidal anti-inflammatory drugs, or NSAIDS, may reduce the risk of colorectal cancer by up to 40 percent, but this protective effect may not extend to long-term smokers, who already face an increased risk of the disease, according to a study led by researchers at Fred Hutchinson Cancer Research Center.

In a large, population-based study comparing risk factors in people with and without colorectal cancer, the researchers found the highest risk of colon cancer to be among long-term smokers of 20 or more years who had never used NSAIDs. The researchers also found that smokers who used NSAIDs were still at an approximate 30 percent higher risk of colon cancer than nonsmokers.

The findings, which appear in the July 1 issue of Cancer Research, arise from the first study of its kind to examine the effects of NSAID use on colorectal-cancer risk among smokers, said first author Victoria Chia, a research associate in the Hutchinson Center's Cancer Prevention Program.

"Smoking has been linked to a modestly increased risk of colorectal cancer, and use of NSAIDs has been shown to significantly decrease the risk of colorectal cancer. We wanted to see if NSAIDs could counteract the adverse effects of smoking with regard to colorectal-cancer risk, and whether these associations differed by tumor characteristics," she said.

In particular, Chia and colleagues were interested in examining the impact of NSAIDs on a certain type of colorectal tumor that may be associated with smoking. Such tumors display microsatellite instability, an acquired genetic characteristic that indicates defects in DNA-repair machinery. Microsatellite instability, or MSI, occurs in approximately 15 percent to 20 percent of colon cancers.

The researchers found a two-fold increased risk of microsatellite-unstable colorectal tumors among long-term smokers who took NSAIDs -- about the same risk as smokers who had not used NSAIDs.

"Given the damage that smokers receive over their lifetime, even strong anti-progression agents, like NSAIDs, may be ineffective," the authors wrote. "NSAIDs may not be able to counteract the long-term effects of smoking, as evidenced by our observation that long-term smokers are at increased risk of colorectal cancer, despite current NSAID use."

The link between smoking and cancer stems from the fact that cigarette smoke contains hundreds of carcinogenic metabolic products that may damage DNA. "This accumulated damage might not be reversible," Chia said. "NSAIDs act to suppress inflammatory processes and may help limit the progression toward cancer. However, people who have microsatellite-unstable tumors may be even more susceptible to the effects of smoking because they already have a reduced capacity to repair DNA, even in the presence of strong anti-inflammatory agents."

Funded by the National Cancer Institute and the National Institutes of Health, the study involved 3,299 Seattle-area residents between the ages of 20 and 74 (mean age 60), approximately half with a history of colon cancer and approximately half without, who served as a control, or comparison group. Cancer cases were identified through the Puget Sound Surveillance, Epidemiology and End Results Program, a population-based registry. Controls were randomly selected to match the distribution of the cases regarding age and sex. Participants were interviewed by telephone about their smoking history and use of aspirin and other NSAID use, among other risk factors. Microsatellite instability was assessed in tumors from 1,202 cases.

Smoking was more common in cancer cases than controls, and NSAID use was more common among controls than cases.

Timing of radiation treatments for colon cancer may need adjusting

Mon, 10 Apr 2006 16:15:37 PST

( from http://www.rxpgnews.com ) Scientists have unexpectedly discovered that mice with the gene defect that causes colon cancer in humans can differ from normal mice in how they respond to radiation treatments. The large intestine carrying the gene defect in mice that received staggered doses of radiation was three to four times more resistant to the radiation than in control mice.

The researchers, led by Bruce Boman, M.D., Ph.D., director of the Division of Genetic and Preventive Medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia and at Jefferson's Kimmel Cancer Center and Dennis Leeper, Ph.D., professor of radiation oncology at Jefferson Medical College, say these results may have implications for treating patients with colon cancer, which is a tumor that frequently has mutations in a gene called APC.

Scientists have known that patients' colon tumors with APC mutations have an increased amount of survivin, a protein that halts the process of programmed cell death. This increase also appears to be associated with a rise in the number of stem cells that sit at the bottom of colonic crypts, tube-like structures that make up the lining of the intestine. Drs. Leeper and Boman wanted to see if there was a difference in stem cell number between normal mice and mice that carry a mutation in APC. To do this, they exposed both normal and mutant mice to radiation, testing their ability to repair the resulting DNA damage. They speculated that increased survivin in the mutant mice might enable more stem cells to survive and affect the response to radiation. The researchers asked if mice with an APC mutation, making them prone to develop colon cancer, are different from normal mice in radiation sensitivity and their ability to repair the damage. Normal cells can repair DNA damage from radiation, Dr. Leeper explains.

They measured the survival of colon crypts in the small and large intestines in normal and mutant mice following radiation exposure, looking at the responses to both single doses of radiation and to staggered or "fractionated" doses of radiation, where the second dose is given five hours after the first dose, again causing the DNA repair to kick in.

"In the normal mouse the radiation-induced damage in the intestine is repaired, just as we expected," Dr. Boman explains. In fact, intestinal cells in both the mutant mouse and normal mouse reacted the same to the single dose of radiation.

But the mutant mice responded differently to the staggered radiation. "When we irradiate five hours later when repair has begun, and damage is being repaired, and then a second dose of radiation is given, the mutant mice are resistant," says Dr. Leeper. More specifically, the Jefferson team found that in the large intestine in the mutant mice, the colon crypt cells were more resistant to radiation by a factor of three to four.

"This has never been observed before to my knowledge," Dr. Leeper says. "This is a novel finding." He notes that the results could have important implications as to how radiation is given to colon cancer patients. "If you are giving radiation once a day, it shouldn't be a problem. But if you are fractionating treatments, given it two or three times a day, this finding could have implications. We would want to make sure that repair processes and signaling receptors come back to baseline before a second dose of chemotherapy is given."

How growth hormone therapy can lead to colon polyps

Mon, 10 Apr 2006 16:09:37 PST

( from http://www.rxpgnews.com ) The use of growth hormone therapy has been linked in some people to the development of colon polyps, a possible precursor to colorectal cancer but medical researchers have debated the extent of a cancer risk.

In addition, the reason for a polyp link to growth hormone has been unclear. But new research from the University of North Carolina at Chapel Hill indicates the probable answer: loss of function of one of a pair of genes that normally would inhibit growth hormone signals inside the cell.

The study also offers a possible molecular marker that could help determine which people taking growth hormone therapy are at increased risk for colon polyps. Researchers already know that colon polyps tend to occur in people who already have excessive amounts of growth hormone, such as those with a disease called acromegaly, or gigantism.

Study senior author Dr. P. Kay Lund, professor of cell and molecular physiology within UNC's School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center, said she and her team had been interested in looking at the effect of a newly discovered inhibitor of cellular growth hormone signaling, suppressor of cytokine signaling-2, or SOCS2.

This molecule limits growth hormone action on the body and organ growth, but its role in growth hormone action on intestine is unknown, Lund said.

"Much of the work on SOCS2 had been done in cell cultures. We wanted to study it in vivo, in laboratory animals, with a focus on how it stops the action of cellular growth hormone."

The researchers thought an ideal way to study this issue would be to use an animal model of acromegaly, laboratory mice having excessive amounts of growth hormone.

The animals were crossed with animals in which the SOCS2 gene was deleted. The breeding generated animals with excessive growth hormone and one or two functional SOCS2 genes, but none with excessive growth hormone and no SOCS2 genes, an unexpected result.

"This meant that excessive growth hormone and no functional SOCS2 is incompatible with successful embryonic development," Lund said.

But there was another surprise: While colon polyps did not develop in animals with excessive growth hormone and two functional SOCS genes, multiple polyps did develop in animals with excessive growth hormone and only one functioning SOCS2 gene.

"We discovered that losing this one copy of SOCS2, this 'haplotype insufficiency,' is enough to cause spontaneous polyp formation in these animals," Lund said, adding that the findings may have implications for humans.

"Haplotype insufficiency animal models are much closer to the normal human variation. Animals expressing just 50 percent normal levels of a protein can be thought of as reflecting the physiological variation that occurs in the general population."

According to Lund, expression levels of SOCS2 measured in, say, 100 people would almost certainly vary by at least 50 percent.

"So this really raises the issue that in a situation of growth hormone excess, such as acromegaly or, possibly, growth hormone therapy, SOCS2 may really be fundamental to dictating your risk of getting abnormalities in the colon."

On the other hand, Lund's research may apply to the variations found in response to growth hormone therapy for the gastrointestinal tract. This would include people with short-bowel syndrome, a group of problems affecting individuals who have had half or more of their small intestine surgically removed. Many people with short bowel syndrome are malnourished because their remaining small intestine is unable to absorb enough water, vitamins and other nutrients from food.

"What has been a puzzle there is that the response to growth hormone in these patients is very variable. Some seem to respond well and get a great benefit from this therapy, and some people don't respond well," Lund said.

"And we found that animals having 50 percent of normal expression levels of SOCS2 show much greater small intestinal growth to growth hormone therapy. So if low SOCS2 enhances the response of the small intestine to growth hormone, it says that patients that have lower SOCS2 may be the ones who favorably respond to this therapy."

Thus, depending on the clinical situation, levels of SOCS2 would either predict who might be at greater risk for colon polyps in the presence of an excess of growth hormone and who might best respond to growth hormone therapy for gastrointestinal conditions such as short bowel syndrome.

"Our future research with SOCS2 will be aimed at studies on human tissue samples to test variations in levels of SOCS2 in the intestine to predict risk of colonic polyps or the response of short bowel syndrome patients to therapeutic growth hormone. Future animal studies will test the role of SOCS2 in cancer models," Lund said.

Review study sets treatment standard for elderly with colon cancer

Sun, 12 Feb 2006 18:52:37 PST

( from http://www.rxpgnews.com ) One of the newest and most potent chemotherapies for colon cancer is as safe and effective for the elderly as it is for younger patients, based on a University of North Carolina at Chapel Hill-led data review.

The analysis focused on nearly 4,000 colon cancer patients who had been enrolled in four large-scale clinical trials that began in the 1990s nationwide and in Europe. The four studies helped establish the value against colorectal cancer of the chemotherapy regimen known as FOLFOX4, a combination of the standard anticancer drugs 5-fluorouracil (5-FU), leucovorin and the new drug oxaliplatin.

"These four studies redefined the treatment standards for colorectal cancer in the United States," said Dr. Richard Goldberg, professor of medicine in UNC's School of Medicine and chief of hematology-oncology at UNC Health Care. "At the time the trials were designed, FOLFOX was experimental; now it is standard."

Goldberg also is associate director of clinical research at UNC Lineberger Comprehensive Cancer Center.

He presented the findings of his review Jan. 25 to a gastrointestinal cancer symposium in San Francisco convened by the American Society of Clinical Oncology, the American Society of Radiation Oncology, the American Gastroenterological Association and the Society of Surgical Oncology.

Although the average age of people nationwide with colorectal cancer is 67 years, individuals older than age 70 accounted for only about 16 percent of patients enrolled in the four FOLFOX clinical trials.

According to Goldberg, this shows that older patients are under-enrolled in clinical trials and also explains why doctors who must manage older colon cancer patients "are not as certain what to do for them as they are for the population that is most represented in clinical trials: those under the age of 65."

In our aging society, an increasing number of people with colorectal cancer are going to be in their seventies and eighties, Goldberg said. "So doctors need to sort out what to do for these patients," he added.

In response to that need, he led a study that reviewed a sample of 3,743 patients drawn from enrollees in each of the FOLFOX trials. His study sought to gather from the data analysis information including whether or not benefits of FOLFOX therapy depended on patient age, older patients had the same side effects as younger patients, older patients received the same doses as younger patients, and whether or not older patients were on the treatment as long as younger patients.

"The major findings were that the benefit of treatment was consistent across all age groups," Goldberg said. "Seventy-year-olds benefited as much as 30-year-olds, and even 75- and 80-year-olds benefited as much as their younger peers."

In terms of side effects, only two laboratory parameters were significantly worse in the older patients than in the younger patients: low white blood cell and low platelet counts. "These low blood counts did not, however, compromise the doses that older patients were able to receive," Goldberg added.

"In side effects that bother patients â nausea, vomiting, diarrhea â older patients fared just as well as younger patients," he said.

Thus, the study showed that age alone should not exclude an otherwise healthy elderly patient from receiving FOLFOX therapy. This includes people who had just undergone surgery for colon cancer, those with advanced disease who are receiving their first chemotherapy treatments and patients with advanced disease who are getting a second treatment regimen.

"Doctors should be willing to offer their patients who are good candidates for treatment the best chemotherapy available in these situations. We know from this study that FOLFOX is safe and effective in both older and younger patients with colorectal cancer," Goldberg said.

Eating red meat could damage DNA by N-nitrosocompounds

Fri, 03 Feb 2006 15:37:37 PST

( from http://www.rxpgnews.com ) Eating a lot of red meat could damage the body's DNA and raise the risk of bowel cancer, a study says.

Previous work suggested that regular meat eaters are significantly more likely to develop bowel cancer but what caused this was not known.

Researchers led by David Shuker at the Dunn Human Nutrition Unit and the Open University, Cambridge, found it could be caused by the presence of substances called N-nitrosocompounds, which form in the large bowel after eating red meat.

They suggest that these compounds combine with DNA, and alter it so that it is more likely to undergo harmful changes or mutations that increase the likelihood of cancer, reported the online edition of BBC News.

The team, which compared a red meat diet and a vegetarian diet, examined cells from the lining of the colon taken from healthy volunteers eating different diets. They found higher levels of DNA damage in the cells taken from people eating red meat.

The discovery allowed researchers to link red meat consumption to an increased risk of bowel cancer and may give them some clues about developing a screening test for very early changes related to the disease, it said.

Large bowel cancer is the second most common cancer in Western countries and nearly one million cases occur each year worldwide. Almost 17,000 people die from the disease each year.

Diet pattern may effect the development of colon cancer

Mon, 19 Dec 2005 22:32:38 PST

( from http://www.rxpgnews.com ) A recent study in The American Journal of Gastroenterology revealed that patterns in diet may effect the development of colorectal adenomas, or precancerous polyps of the colon.

In this study, over 1500 patients underwent baseline colonoscopy to remove existing polyps. They were then given a survey about their diet. After a period of one and then four years later, the group underwent follow-up colonoscopies to determine if any polyps had returned. Those who had consumed diets higher in processed meats showed a greater risk of developing recurrent colorectal adenomas. Those with diets high in certain white meats, like chicken, were less prone to this risk.

"Our results are consistent with prior studies that suggest certain dietary factors may be important in the development of colon polyps and cancer," states Douglas Robertson, lead researcher of the study and Chief of the Section of Gastroenterology at the VA Medical Center in White River Junction, Vermont.

Previous studies have explored whether fiber intake effects the growth and development of colorectal adenomas and cancer, however, this study found no significant evidence to suggest an association. The same was determined for dietary intake of fat and red meat.

According to the National Cancer Institute and U.S. National Institutes of Health, Colorectal cancer is the third most common type of non-skin cancer in men (after prostate cancer and lung cancer) and in women (after breast cancer and lung cancer). It is the second leading cause of cancer death in the United States with more than 57,000 people dying from colorectal cancer each year.

High dietary fiber intake do not reduce colorectal cancer risk

Wed, 14 Dec 2005 16:52:38 PST

( from http://www.rxpgnews.com ) In an analysis combining data from 13 studies, high intake of dietary fiber was not associated with reduced risk of colorectal cancer, according to a study in the December 14 issue of JAMA.

Dietary fiber has been hypothesized to reduce the risk of colorectal cancer, according to background information in the article. However, the results of numerous epidemiological studies have been inconsistent. Ecological correlation studies and many case-control studies have found an inverse association between dietary fiber intake and risk of colorectal cancer. But most prospective cohort studies have found no association between dietary fiber intake and risk of colorectal cancer or adenomas (precursors of colorectal cancer), and randomized clinical trials of dietary fiber supplementation have failed to show reductions in the recurrence of colorectal adenomas.

Yikyung Park, Sc.D., of the Harvard School of Public Health, Boston, and colleagues evaluated the association between dietary fiber intake and risk of colorectal cancer by reanalyzing the primary data from 13 prospective cohort studies (Pooling Project of Prospective Studies of Diet and Cancer). The pooled analysis included 725,628 men and women who were followed-up for 6 to 20 years across studies.

During the follow-up, 8,081 colorectal cancer cases were identified. Among the studies, median (midpoint) energy-adjusted dietary fiber intake ranged from 14 to 28 g/d in men and from 13 to 24 g/d in women. The major source of dietary fiber varied across studies with cereals as a major contributor to dietary fiber intake in the European studies, and fruits and vegetables as the main sources in the North American studies.

In the age-adjusted model, dietary fiber intake was significantly associated with a 16 percent lower risk of colorectal cancer in the highest quintile compared with the lowest. This association was attenuated slightly but still remained statistically significant after adjusting for nondietary risk factors, multivitamin use, and total energy intake. Additional adjustment for dietary folate intake further weakened the association. In the final model, which further adjusted for other dietary factors, such as red meat, total milk, and alcohol intake, only a nonsignificant weak inverse association was found. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer.

"The association between dietary fiber intake and risk of colorectal cancer has been inconsistent among observational studies and several factors may explain the disparity: potential biases in each study, the failure to adjust for covariates in the multivariate models, and the range of dietary fiber intake," the authors write.

"In conclusion, we did not find support for a linear inverse association between dietary fiber intake and risk of colorectal cancer in a pooled analysis of 13 prospective cohort studies. Although high dietary fiber intake may not have a major effect on the risk of colorectal cancer, a diet high in dietary fiber from whole plant foods can be advised because this has been related to lower risks of other chronic conditions such as heart disease and diabetes," the researchers write.

Chemotherapy after stage 3 colon cancer increases survival

Fri, 09 Dec 2005 18:47:38 PST

( from http://www.rxpgnews.com ) More patients with stage III colon cancer are receiving chemotherapy after surgery, with an associated significant increase in 5-year survival, according to a study in the December 7 issue of JAMA. The study also found that women, blacks and the elderly were less likely to receive this treatment.

According to background information in the article, based on the results of two trials, the National Institutes of Health Consensus Conference recommended in 1990 that adjuvant chemotherapy (chemotherapy after the primary tumor has been removed by some other method, as in surgery or radiation therapy) be given to all patients with stage III colon cancer who were not enrolled in a clinical trial. However, as with most recommendations, it is not clear to what extent they are followed or contribute to outcome in the general population.

J. Milburn Jessup, M.D., of the National Cancer Institute, Rockville, Md., and colleagues assessed to what extent the 1990 Consensus Conference recommendation has been followed in the community and whether adjuvant chemotherapy has improved the 5-year survival of patients with stage III colon cancer. The study included data from 85,934 patients with stage III colon cancer from 560 hospital cancer registries who were entered into the National Cancer Data Base (NCDB) between 1990 and 2002. The data included standard clinical, pathological, and first course of treatment variables.

The researchers found an increase in the use of adjuvant chemotherapy for all patients with stage III colon cancers from 39 percent of patients in 1990 to 64 percent in 2002, but use was lower in black, female, and elderly patients. The difference in 5 year survival increased from an 8 percent improvement in the 1991 subgroup to 16 percent in the 1997 subgroup that received adjuvant chemotherapy compared with surgery alone. The researchers also found that adjuvant chemotherapy increases survival in elderly patients as much as it does in younger patients. However, the benefit of adjuvant chemotherapy in blacks and those with high-grade cancers is not as great.

Future studies are needed to identify whether newer agents such as irinotecan and oxaliplatin may be more effective in patients with high-grade cancers or in blacks than the 5-fluorouracil and leucovorin regimens that were dominant during the time that the cohorts reported herein were followed up for survival, the authors conclude.

In an accompanying editorial, Eric Van Cutsem, M.D., Ph.D., of University Hospital Gasthuisberg, Leuven, Belgium, and Frederico Costa, M.D., of Hospital Sírio Libanês, São Paulo, Brazil, comment on the study by Jessup et al.

The central issue regarding adjuvant chemotherapy is the difficulty in assessing its real benefit for an individual patient. The recommendation is generally based on the proof of efficacy in a selected population at risk for disease recurrence. The decision-making process is always complex. On the one hand, the physicians understanding of the potential benefit is influenced by his or her own prejudice; on the other hand, the patients confidence is influenced by beliefs and fear. Factors such as comorbidities, socioeconomic status, and low adherence to therapy are among the well-described causes for not using adjuvant chemotherapy. Ongoing studies of molecular markers for colorectal cancer should help determine which patients benefit most from adjuvant therapy.

Even though causes for recommending or not recommending adjuvant chemotherapy are multifactorial, Jessup et al observed an increase in the use of adjuvant chemotherapy over time. It is not clear why it took so many years for a majority of patients to receive adjuvant treatment despite the clear demonstration of a survival benefit. Hopefully, further progress in the knowledge of adjuvant therapy will have a more rapid influence on clinical practice in the near future, the authors conclude.

Preventing bowel cancer in high risk families by screening with colonoscopy

Tue, 25 Oct 2005 21:52:38 PST

( from http://www.rxpgnews.com ) BOWEL cancer rates could be reduced by up to 80 per cent in people with a moderate family history of the disease by screening with colonoscopy, according to new research published in the British Medical Journal.

But the research shows that most people, even those who have two or three relatives with the disease, do not need to be screened before the age of 45 or need to be screened very frequently.

The new research from Cancer Research UK could help prevent thousands of cases of bowel cancer and guide doctors in how best to use precious screening resources.

As many as a third of the 34,000 bowel cancer cases diagnosed in the UK each year occur in someone with a family history of the disease. A small proportion of these people have a fault in a specific gene which leads to a condition called hereditary nonpolyposis colorectal cancer (HNPCC) but the majority of cases have no known genetic fault.

HNPCC families are currently screened with colonoscopy every two years from the age of 25 and the new research supports this practice, estimating that screening reduces cancer deaths in this group by up to 70 per cent.

But until now, there has been no strong evidence on how to deal with the remaining majority of people with a family history of bowel cancer. The new study shows an 80 per cent decrease of tumours by screening this group.

Screening with colonoscopy means that pre-cancerous growths can be detected and removed before they progress to cancer.

Study author, Professor Peter Sasieni of Cancer Research UK explains: "We now know that screening with colonoscopy prevents the majority of bowel cancers in people with a family history. The study also shows that screening isn't necessary before the age of 45 and, even then, it only needs to be performed every five years or so.

"This is good news for people with a family history because it means they can dramatically reduce their risk of cancer by going for occasional screening.

"It's also good news for hospitals because, in most cases, this will mean less intensive screening and less of a drain on resources."

The research took place at Cancer Research UK's family cancer clinic at St Mark's Hospital, Middlesex. The study involved over 1,600 people with at least one close relative diagnosed with bowel cancer. Study participants were screened regularly and monitored for up to 16 years. The number of cancers found was compared to the number of cancers expected in a similar, unscreened population.

A national bowel screening programme will be phased in across England over three years, starting in April 2006. Men and women aged between 60-69 years old will be screened every two years*.

Professor John Toy, Cancer Research UK's Medical Director, says: "With the introduction of a national screening programme for bowel cancer due to begin next year, we anticipate a major increase in the number of people referred for colonoscopy.

"This research is important because it shows how most cancers can be prevented in people with a family history. It also indicates how resources can best be used and help to minimise unnecessary colonoscopies for people."

How TGFBR1*6A contributes to cancer development

Thu, 06 Oct 2005 21:35:38 PST

( from http://www.rxpgnews.com ) Transforming growth factor beta (TGF-beta) is a potent naturally occurring inhibitor of cell growth, according to background information in the article. It exerts its action by binding to type I (TGFBR1) and type II (TGFBR2) receptors located on the cell membrane. Increased cell growth due to decreased TGF-beta growth inhibition may contribute to cancer development. TGFBR1*6A is a common polymorphism (variation) of TGFBR1. Previous studies have shown that TGFBR1*6A is one of the first candidate tumor susceptibility alleles (DNA codings of the same gene) that is found in a large proportion of the general population (13.7 percent) and significantly increases cancer risk by approximately 24 percent. How TGFBR1*6A contributes to cancer development is largely unknown.

Boris Pasche, M.D., Ph.D., of Northwestern University Feinberg School of Medicine, Chicago, and colleagues conducted a study that included 531 patients with a diagnosis of head and neck cancer, colorectal cancer, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. Multiple genetic testing of the cancer cells was conducted.

The researchers found that TGFBR1 mutated into TGFBR1*6A, i.e. was somatically acquired, in 13 of 44 (29.5 percent) colorectal cancer metastases, in 4 of 157 (2.5 percent) of colorectal tumors, in 4 of 226 (1.8 percent) head and neck primary tumors, and in none of the 104 patients with breast cancer.

While TGF-beta inhibits the growth of normal cells, cancer cells secrete larger amounts of TGF-beta than their normal counterparts. The researchers showed that, in the presence of TGF-beta, the growth of cancer cells that carry the TGFBR1*6A gene is 55 percent greater than cancer cells that do not carry this gene, indicating that TGFBR1*6A give cancer cells a selective advantage. This, together with the findings that TGFBR1*6A is acquired by tumors, may explain why half of all liver metastases from colorectal cancer carried the TGFBR1*6A gene while it is only found in 14 percent of the general population.

"...individuals who carry the *6A allele, either in the germline or somatically acquired by the tumor, may have a greater likelihood of developing metastases than individuals who do not carry this allele. *6A may therefore serve as a useful biomarker in cancer." The authors add that TGFBR1*6A may bestow cancer cells with a growth advantage in the presence of TGF-beta.

"Since 13.7 percent of the general population and 17.1 percent of patients with a diagnosis of cancer carry at least 1 copy of the *6A allele, our findings may have substantial public health importance. The high frequency of *6A carriers in the general population and the moderately increased risk of breast, colon, and ovarian cancer that it confers implies that the dominant effects of *6A have an incomplete penetrance. Additional studies are needed to determine which environmental and genetic factors may modify the penetrance of *6A in these tumor types," the researchers write.

"The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer."

Investigating the link between being overweight and colon cancer

Sun, 04 Sep 2005 20:16:38 PST

( from http://www.rxpgnews.com ) Researchers at the University of Leeds are investigating the link between being overweight and the risk of colon cancer with a grant of £98,587 from the world cancer research fund.

Professor Mark Hull, who is leading the research, and his team are testing whether being overweight leads to inflammation of the colon and whether this explains the increase in the risk of cancer developing.

It is thought that inflammation creates an imbalance in cell turnover between cells dying and new cells forming, so that cells can then become cancerous. Laboratory studies have shown that an eight per cent reduction in body weight leads to a 40 per cent drop in this cell turnover and so maintaining a healthy weight may be an important factor in avoiding colon cancer along with other measures such as eating plenty of fruit and vegetables and taking exercise.

Professor Mark Hull, from the University of Leeds school of medicine said: We are extremely grateful to the world cancer research fund for this grant. On average, across the entire population, you have a 1 in 50 chance of developing colon cancer so it is vitally important that people should take preventative measures to try and avoid this disease, which includes maintaining a healthy weight.

Dr Elaine Stone, senior research manager at the world cancer research fund said: Our funding is vital for research of this kind. We believe that many cancers can be avoided by eating a healthy diet, being physically active and maintaining a stable weight throughout life and this research will add to the wealth of information that already exists supporting this.

The team are working with a group of extremely obese patients who are undergoing stomach bypass surgery that will enable them to lose 25-30kg (between 3 stone 9lbs and 4 stone 7 lbs) in the six months following surgery. The results of this operation mean when food is eaten only a certain amount of nutrients are absorbed by the body as the food enters the digestive system lower down.

A sample of bowel is taken from the patient before the surgery and the level of inflammation will be measured. Six months following surgery patients will be invited to return to the hospital for a follow up to see whether this has reduced.

There are 200,000 overweight people in Leeds and every year the hospital performs about 50 stomach bypass operations. Prior to surgery the patient will have undergone a variety of other weight loss interventions such as, advice on weight control, diet, exercise and lifestyle, drug therapy, referral to specialist weight loss clinics, behavioural therapy and low calorie and very low calorie diets.

Aspirin Use Reduces Colorectal Cancer Risk Among Women

Wed, 24 Aug 2005 19:21:38 PST

( from http://www.rxpgnews.com ) Women who took two or more aspirin or NSAIDs per week for more than 10 years significantly reduced their risk of colorectal cancer, according to an article in the August 24/31 issue of JAMA.

Recent randomized intervention trials have demonstrated that regular use of aspirin in patients with a history of colorectal adenoma (benign tumor) or cancer reduces the risk of recurrent adenoma within 1 to 3 years, according to background information in the article. However, whether long-term use of aspirin similarly reduces the risk of colorectal cancer and, if so, at what dose, has been unclear.

Andrew T. Chan, M.D., M.P.H., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues examined the influence of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of colorectal cancer in a large group of women. The study included 82,911 women, enrolled in the Nurses' Health Study, who have been providing data on medication use biennially since 1980 and followed up through June 1, 2000.

Over the 20-year period, 962 cases of colorectal cancer were documented. Among women who regularly used aspirin (2 or more standard [325-mg] tablets per week), there was a 23 percent reduced relative risk for colorectal cancer compared with nonregular users. However, significant risk reduction was not observed until more than 10 years of use. The benefit appeared related to dose: compared with women who reported no use, the relative risk for cancer was 10 percent greater for women who used 0.5 to 1.5 standard aspirin tablets per week; 11 percent lower with 2 to 5 aspirin per week; 22 percent lower with 6 to 14 aspirin per week; and 32 percent lower with more than 14 aspirin per week. Women who took more than 14 aspirin per week for longer than 10 years had a 53 percent lower relative risk for colorectal cancer. A similar dose-response relationship was found for nonaspirin NSAIDs.

The incidence of reported major gastrointestinal bleeding events per 1000 person-years also appeared to be dose-related: 0.77 among women who denied any aspirin use; 1.07 for 0.5 to 1.5 standard aspirin tablets per week; 1.07 for 2 to 5 aspirin per week; 1.40 for 6 to 14 aspirin per week; and 1.57 for more than 14 aspirin per week.

"Our study supports a possible role for aspirin in cancer prevention, which has been demonstrated by prior adenoma recurrence trials. However, any substantial impact of aspirin on cancer necessitates early initiation and prolonged, consistent use. Moreover, optimal chemoprevention may require substantially higher doses of aspirin than currently recommended for the prevention of cardiovascular disease. Many toxicities of aspirin, including gastrointestinal bleeding, are dose-dependent. Thus, future studies will need to thoroughly consider the risk-benefit profile for aspirin/NSAID chemoprevention among various risk groups and compare such a strategy with other potential prevention efforts," the authors conclude.

Study Examines Racial Disparities in Colon Cancer Treatment

Fri, 19 Aug 2005 04:58:38 PST

( from http://www.rxpgnews.com ) Elderly black and white colon cancer patients are equally likely to consult with medical oncologists, but they do not receive recommended adjuvant treatment at the same rates after this consultation, according to a new study.

Studies have shown that black patients are less likely than white patients to receive screening and diagnostic tests and some treatments.

A 2001 study, published in the Journal of the National Cancer Institute, reported that black patients were less likely than white patients to receive recommended chemotherapy for stage III colon cancer. To determine whether health care system factors, including those related to the hospitals in which patients are treated and the doctors who treat them, may help explain this disparity, Laura-Mae Baldwin, M.D., M.P.H., of the University of Washington in Seattle, and colleagues used data from several sources to examine receipt of chemotherapy after stage III colon cancer resection in 5,294 elderly black and white Medicare-insured patients.

Nearly 80% of both black and white patients consulted with a medical oncologist. Among those who received a consultation, 70.4% of white patients but only 59.3% of black patients received chemotherapy. The disparity was highest among patients ages 66 to 70, and approximately half of this disparity was attributable to patient, physician, hospital, and environmental factors, 27% to surgical length of stay and neighborhood socioeconomic status, and only 12% to health systems. The authors conclude that more qualitative research is needed to understand the factors that contribute to the lower receipt of chemotherapy by black patients.

Panitumumab gets fast track designation for metastatic colorectal cancer

Mon, 01 Aug 2005 23:26:38 PST

( from http://www.rxpgnews.com ) Amgen and Abgenix, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted fast track designation for panitumumab, an experimental fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr), for patients with metastatic colorectal cancer who have failed standard chemotherapy treatment.

"We are advancing the development of panitumumab with the hope of offering patients a new treatment option in their fight against metastatic colorectal cancer," said Willard Dere, M.D., chief medical officer and senior vice president of global development at Amgen.

Under the FDA Modernization Act of 1997, fast track designation allows the FDA to accept, on a rolling basis, portions of a marketing application for review prior to the completion of the final registrational package. Fast track designation may potentially expedite the review of a drug that is intended for the treatment of a serious life- threatening condition and demonstrates the potential to address an unmet medical need for such a condition.

In light of this fast track designation, Amgen and Abgenix are working toward initiating the submission of the Biologics License Application (BLA) for panitumumab in patients who have failed prior standard chemotherapy, including irinotecan and oxaliplatin, by the end of 2005. The completed submission of the BLA could extend into the first quarter of 2006, depending on timing and outcome of clinical data. FDA has previously indicated that data from one pivotal trial, once completed, could be acceptable with additional data from other pending studies to support a submission for marketing approval in the United States.

"Panitumumab is the first fully human monoclonal antibody to inhibit EGFr, and fast track designation represents an important milestone in its development," said Bill Ringo, chief executive officer at Abgenix. "We are one step closer to bringing this promising new treatment to patients with advanced colorectal cancer."

Patients and physicians can access www.amgentrials.com for more information about ongoing panitumumab clinical trials.

About Panitumumab

Co-developed by Amgen and Abgenix, panitumumab is an investigational product in a novel class of targeted cancer treatments called epidermal growth factor receptor (EGFr) inhibitors. Panitumumab (formerly ABX-EGF) is the first fully human monoclonal antibody directed against EGFr and is being evaluated as both a monotherapy and in combination with other agents for the treatment of various types of cancer, including colorectal, lung and kidney. Panitumumab was generated with Abgenix's XenoMouse(R)(1) technology, which creates a fully human monoclonal antibody that contains no murine (mouse) protein. The fully human nature of panitumumab may result in a safety profile with a low incidence of infusion reactions, antigenicity and allergic response. These are attributes currently being investigated in clinical trials. Pivotal clinical studies evaluating panitumumab as a third-line monotherapy in colorectal cancer patients are ongoing with an every-other-week dosing regimen.

About the Epidermal Growth Factor Receptor (EGFr)

Although EGFr normally helps regulate the growth of many different cells in the body, EGFr can also stimulate cancer cells to grow. In fact, many cancer cells actually require signals mediated by EGFr for their survival. Residing on the surface of these tumor cells, EGFr is activated when naturally occurring proteins in the body, epidermal growth factor (EGF) or transforming growth factor alpha (TGFa), bind to it. This binding changes the shape of EGFr, which, in turn, triggers internal cellular signals that stimulate tumor cell growth.

Panitumumab binds to EGFr, preventing EGF and TGFa from binding to the receptor and interfering with the signals that would otherwise stimulate growth of the cancer cell and allow it to survive.

Updated Phase II COFU Trial Data

Mon, 20 Jun 2005 18:55:38 PST

( from http://www.rxpgnews.com ) ADVENTRX Pharmaceuticals, Inc. (Amex:ANX) today announced response data from all 48 measurable patients in its 50-patient Phase II trial with CoFactor(TM) and 5-fluorouracil (5-FU) as a first-line treatment for metastatic colorectal cancer. CoFactor is ADVENTRX's biomodulator designed to enhance the effects of the widely used cancer drug, 5-FU. A poster of these results was presented at the 7th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Updated Phase II COFU trial data

-- Sixty-five percent, or 31 patients, treated with CoFactor and 5-FU achieved clinical benefit, defined as tumor response or stable disease following study therapy.

-- Objective response data showed 38%, or 18 patients, responded to treatment with CoFactor and 5-FU, surpassing the trial's primary endpoint objective of 25%. Objective response is defined as all patients having complete or partial responses, whose tumor measurements are confirmed by MRI or CT scan by repeat assessment performed no less than four weeks after the criteria for response is first met. A complete response is a complete disappearance of the tumor; partial response is at least a 50% reduction in total tumor size as defined by World Health Organization (WHO) criteria.

-- Thirteen patients exhibited stable disease and 17 have progressive disease. Stable disease is less than a 50% reduction in total tumor size; and progressive disease is at least a 25% increase in tumor size at the end of the treatment cycle, as measured by CT or MRI scans.

-- No grade 3 or 4 gastrointestinal or hematological toxicities were recorded demonstrating the treatment regimen of CoFactor plus 5-FU was well tolerated. Toxicity grades were determined in accordance with the National Cancer Institute's Common Terminology Criteria for Adverse Events grading system. The most common adverse events were diarrhea, nausea and vomiting, none of which were grade 3 or 4. There was a single case of grade 3 watery eye, and a grade 3 bowel obstruction not related to study drug. This safety data was measured in all 50 patients enrolled in the trial.

"These results further confirm that CoFactor plus 5-FU present a viable alternative for patients with metastatic colorectal cancer as it achieves increased response rates without high levels of toxicity, compared with leucovorin plus 5-FU," said Evan M. Levine, president and CEO for ADVENTRX. "Patients in this trial continue to be followed for time-to-tumor progression and overall survival and we look forward to announcing this data later this year."

Cellia Habita, M.D., Ph.D., senior vice president of medical and clinical affairs of ADVENTRX, presented poster # 371 entitled, "A Simon two stage study of CoFactor (CO) with 5-fluorouracil (FU) as first line treatment in metastatic colorectal cancer (mCRC)." This abstract is available via ADVENTRX's Web site at www.adventrx.com.

About CoFactor

CoFactor (ANX-510) is a folate-based biomodulator drug developed to enhance the activity of the widely used cancer chemotherapeutic 5-FU. Data from previous clinical trials in Europe have demonstrated clinical benefit and improved overall median survival in patients with advanced tumors, including colorectal, pancreatic and breast. In comparison to leucovorin, CoFactor creates more stable binding of the active form of 5-FU, FdUMP, to the target enzyme, thymidylate synthase (TS). CoFactor bypasses the chemical pathway required by leucovorin to deliver the active form of folate, allowing 5-FU to work more effectively. This improves 5-FU performance and lowers toxicity.

About the Phase II COFU trial

The Phase II clinical trial is an open label, single arm Simon 2 stage study design to assess the safety and efficacy of CoFactor plus 5-FU as a first line treatment of metastatic colorectal cancer. Patients enrolled in this trial are age 18 and older with ECOG 0-2 and measurable metastatic colorectal cancer, with or without adjuvant 5-FU/leucovorin, irinotecan, or oxaliplatin, but no prior chemotherapy for metastatic disease. Patients may receive more than two cycles each consisting of CoFactor 60 mg/m2 and 5-FU 450 mg/m2 (weekly IV bolus) for six consecutive weeks, followed by a 14 day rest period, which is defined as a cycle. Pre-established response criteria are greater than four responders of 23 patients for stage one, and greater than 12 responders of 48 patients for the full trial. The trial is being conducted in the U.S. and Europe under a U.S. investigational new drug application.

FDA Approves Capecitabine for Adjuvant Treatment of Colon Cancer

Fri, 17 Jun 2005 09:42:38 PST

( from http://www.rxpgnews.com ) Roche announced today that the U.S. Food and Drug Administration (FDA) has approved Xeloda(R) (capecitabine) -- an innovative oral chemotherapy -- for the adjuvant (post-surgery) treatment of patients with Dukes' C colon cancer.

Adjuvant chemotherapy is the standard treatment approach for Dukes' C colon cancer (cancer that has spread to the lymph nodes), where chemotherapy is given after the tumor has been surgically removed. This approval will now give patients who have undergone complete resection of their primary tumor the option of an oral chemotherapy when fluoropyrimidine therapy alone is preferred.

The adjuvant indication was based on data from the X-ACT (Xeloda in Adjuvant Colon Cancer Therapy) trial. This pivotal trial showed that Xeloda met its primary endpoint of non-inferiority to 5-FU/LV for disease-free survival (DFS). At this time, neither Xeloda nor combination chemotherapy has been shown to prolong overall survival; combination chemotherapy has demonstrated an improvement in disease-free survival compared to 5-FU/LV.

Although intravenous 5-FU/LV (also known as the Mayo Clinic Regimen) has been the foundation of such treatment for 40 years, researchers have long recognized the need for more convenient treatment regimens. The Mayo Clinic intravenous regimen for colon cancer can require up to 30 clinic visits over the 24-week treatment course, compared to a minimum of eight visits for patients receiving Xeloda.

"What this means is that now thousands of additional colon cancer patients could have the option of using a convenient and effective oral chemotherapy earlier in the treatment of their disease. With Xeloda, they can replace hours of cumbersome intravenous therapy in a clinic with a pill that can be taken at home," said Dr. Howard Burris of the Sarah Cannon Research Institute in Nashville, Tennessee. "This new indication for Xeloda is great news for colon cancer patients."

The three-year disease-free survival rates were 66 percent for patients treated with Xeloda, compared to 62.9 percent treated with 5-FU/LV. The overall incidence of grade 3-4 toxicities were similar between Xeloda and 5-FU/LV. Patients treated with Xeloda experienced fewer severe (grade 3-4) toxicities for certain events including less stomatitis and neutropenic fever/sepsis when compared to those receiving intravenous 5-FU/LV. Hand-and- foot syndrome -- a common toxicity seen with fluoropyrimidines -- was higher in the Xeloda arm in this study (grade 3-4).

Xeloda is a drug taken orally which is activated into a chemotherapy agent by a naturally-occurring enzyme called thymidine phosphorylase, or TP. Once in contact with TP, which is expressed at higher levels by colorectal cancers, Xeloda is transformed inside the tumor into 5-FU, an anti-cancer drug.

"Roche applauds the FDA's decision today. With this approval, even more colon cancer patients will have access to an oral treatment option in the adjuvant setting, and can benefit from the convenience of a proven, effective oral chemotherapy," said Lars Birgerson, M.D., Ph.D., Vice President, Medical Affairs, Roche U.S. "The approval underscores our ongoing commitment to advancing cancer treatment for all patients."

Roche has an ongoing study program looking at Xeloda in combination with other chemotherapies and targeted therapies.

"More than 145,000 Americans will be diagnosed with colon cancer this year, so it's important that the cancer community continually seeks to improve available treatment options," said Carolyn Aldige, president of the Cancer Research and Prevention Foundation. "We commend Roche's commitment, as evidenced by today's FDA approval, to bringing effective and more convenient options to patients with colon cancer."

About Colon Cancer and Adjuvant Treatment

Colorectal cancer (cancer of the colon or rectum) is the third leading cause of cancer-related deaths in the United States, and the second worldwide. The American Cancer Society (ACS) estimates that in 2005, more than 145,000 Americans will be diagnosed with colorectal cancer and more than 56,000 will die from the disease -- a number that could be cut in half if Americans followed ACS recommendations to begin screening at age 50. Benchmarks provided in the National Cancer Data Base (NCDB) show approximately 24,000 new patients will be diagnosed with Dukes' C colon cancer, the specific type and stage of the disease studied in X-ACT. Adjuvant treatment (chemotherapy following surgery) is one of the most common treatment strategies in patients diagnosed during the later stage of the disease.

About Xeloda

Xeloda is indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Xeloda was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither Xeloda nor combination therapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent Xeloda in the adjuvant treatment of Dukes' C colon cancer.

Xeloda is covered by Medicare.

Xeloda Safety Information

A clinically important drug interaction between Xeloda and warfarin has been demonstrated; altered coagulation parameters and/or bleeding and death have been reported. Clinically significant increases in prothrombin time (PT) and INR have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda. For patients receiving both drugs concomitantly, frequent monitoring of INR or PT is recommended. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Xeloda is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil, and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Xeloda is contraindicated in patients with severe renal impairment. For patients with moderate renal impairment, dose reduction is required. Xeloda can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored. Patients 80 and older receiving Xeloda monotherapy may experience a greater incidence of grade 3 or 4 adverse events. Xeloda may cause fetal harm when given to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Xeloda. It is recommended that nursing be discontinued when using Xeloda. Men should use birth control when using Xeloda.

Common adverse events in the adjuvant setting were: diarrhea (Xeloda 47%, 5-FU/LV 65%), nausea (Xeloda 34%, 5-FU/LV 47%), stomatitis (Xeloda 22%, 5- FU/LV 60%), vomiting (Xeloda 15%, 5-FU/LV 21%,), fatigue (Xeloda 16%, 5-FU/LV 16%) and hand-foot syndrome (Xeloda 60%, 5-FU/LV 9%). As with any cancer therapy, there is a risk of side effects, and these are usually manageable and reversible with dose modification or interruption.

FDA Approves Oral Chemotherapy Pill for Colon Cancer

Fri, 17 Jun 2005 09:21:38 PST

( from http://www.rxpgnews.com ) THE FDA HAS APPROVED THE ORAL CHEMOTHERAPY, XELODA, TO TREAT DUKES C COLON CANCER PATIENTS WHO HAVE UNDERGONE COMPLETE RESECTION OF THE PRIMARY TUMOR WHEN FLUOROPYRIMIDINE THERAPY ALONE IS PREFERRED.

THE ADJUVANT INDICATION WAS BASED ON DATA FROM THE X-ACT TRIAL. THIS PIVOTAL TRIAL SHOWED THAT XELODA MET ITS PRIMARY ENDPOINT OF NON-INFERIORITY TO 5-FU/LV FOR DISEASE-FREE SURVIVAL. AT THIS TIME, NEITHER XELODA NOR COMBINATION CHEMOTHERAPY HAS BEEN SHOWN TO PROLONG OVERALL SURVIVAL; COMBINATION CHEMOTHERAPY HAS DEMONSTRATED AN IMPROVEMENT IN DISEASE FREE SURVIVAL COMPARED TO 5-FU/LV.

DR. HOWARD BURRIS OF THE SARAH CANNON RESEARCH INSTITUTE IN NASHVILLE SAYS THIS APPROVAL IS IMPORTANT FOR PATIENTS.

"It provides a safe, effective, alternative means offering patients the opportunity to receive pill therapy in the comfort of their home rather than needing to come into the clinic for repeated IV injections."

LIKE ALL CHEMOTHERAPY DRUGS, XELODA MAY NOT BE RIGHT FOR SOME PATIENTS. PATIENTS TAKING WARFARIN SHOULD CONSULT THEIR PHYSICIANS. IM CHRIS ALLEN.

More about Xeloda

Indication:

Xeloda is indicated as a single agent for adjuvant treatment in patients with Dukes C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Xeloda was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither Xeloda nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent Xeloda in the adjuvant treatment of Dukes C colon cancer.

Xeloda is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with Xeloda monotherapy. Use of Xeloda instead of 5-FU/LV in combinations has not been adequately studied to assure safety of preservation of the survival advantage.

Xeloda in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracyline- containing chemotherapy.

Xeloda monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline- containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalence. Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within six months of completing treatment with an anthracycline-containing adjuvant regimen.

Safety:

A clinically important drug interaction between Xeloda and warfarin has been demonstrated; altered coagulation parameters and/or bleeding and death have been reported. Clinically significant increases in prothrombin time (PT) and INR have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda. For patients receiving both drugs concomitantly, frequent monitoring of INR or PT is recommended.

Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Xeloda is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil, and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Xeloda is contraindicated in patients with severe renal impairment. For patients with moderate renal impairment, dose reduction is required. Xeloda can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored. Patients 80 and older receiving Xeloda monotherapy may experience a greater incidence of grade 3 or 4 adverse events. Xeloda may cause fetal harm when given to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Xeloda. It is recommended that nursing be discontinued when using Xeloda. Men should use birth control when using Xeloda.

Common adverse events in the adjuvant setting were: diarrhea (Xeloda 47%, 5-FU/LV 65%), nausea (Xeloda 34%, 5-FU/LV 47%), stomatitis (Xeloda 22%, 5- FU/LV 60%), vomiting (Xeloda 15%, 5-FU/LV 21%), fatigue (Xeloda 16%, 5-FU/LV 16%) and hand-foot syndrome (Xeloda 60%, 5-FU/LV 9%). As with any cancer therapy, there is a risk of side effects, and these are usually manageable and reversible with dose modification or interruption.

Chemotherapy options improve for patients with advanced colorectal cancer

Tue, 07 Jun 2005 11:58:38 PST

( from http://www.rxpgnews.com ) For the first time, researchers have shown that a chemotherapy regimen of capecitabine plus oxaliplatin (CAPOX) is as safe and effective as infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) in the first-line treatment of metastatic colorectal carcinoma (MCRC). The findings are reported today at the 2nd ESMO Scientific & Educational Conference (ESEC) in Budapest, Hungary.

"We conducted this phase III study because the combination of oral capecitabine and oxaliplatin showed promising effects in different phase II studies. The idea of this study was to look whether CAPOX can replace the standard treatment of iv. 5-FU/folinic acid in patients with MCRC", said lead author Dr. Hendrik-Tobias Arkenau, from Clinic Bremen East in Germany.

From 2002 to 2004, the authors randomly assigned 476 patients who had not undergone previous chemotherapy to receive either FUFOX (5-fluorouracil (5-FU) 2000mg/m² 24h infusion, folinic acid 500mg/m², oxaliplatin 50mg/m² d1,8,15,22; q5 wks) or CAPOX (capecitabine 1000mg/m² bid d1-14, oxaliplatin 70mg/m² d1 and 8; q3 wks).

So far, based on an analysis of 2541 treatment cycles (1026 FUFOX, 1515 CAPOX), both regimens are comparably toxic and showed similar response rates (ITT-RR: 50% FUFOX and 47% CAPOX, p=NS).

Median length of time without progression of disease was 34.7 weeks in the FUFOX arm and 30.3 weeks in the CAPOX arm, respectively, a difference that was not statistically different (p=0.1), the authors found. Additionally, both treatment arms showed similar overall survival, FUFOX 74.9 weeks and CAPOX 70.9 weeks, p=0.72.

The authors conclude that CAPOX shows comparable efficacy and toxicity profiles compared to the FUFOX regimen in patients chemonaive MCRC.

"This study is important for patients because the CAPOX regimen is more convenient to administer. Patients will appreciate needing to come only twice in three weeks as outpatients to receive the 2 hourly oxaliplatin dose. Especially in the palliative setting of MCRC, patients gain more autonomy and improved quality of life," Dr. Arkenau said.

"We hope that oral capecitabine plus oxaliplatin will become the new standard treatment in first-line treatment for patients with metastatic colorectal carcinoma."

Commenting on the study, Professor Hans Joachim Schmoll of Martin-Luther-Universität Halle-Wittenberg in Germany said the results of the trial "are of major importance for the clinical routine, at least for those patients who would like to avoid intravenous infusional protocols, ports and pumps."

The 5-FU-infusion in combination with cytostatic agents like oxaliplatin or irinotecan in patients with colorectal cancer is complicated and needs support and a pump for the patient, he said. This is a cause of major discomfort, meaning it is important to investigate alternatives substituting the infusion of 5-FU by oral agents.

"This study for the first time shows that an oral based Cap/Ox regimen is able to substitute for the complex intravenous 5-FU 2-drug- or 3-drug-combination in colorectal cancer. Large trials are underway to definitely answer this question with several thousand patients; however, the results of these studies will not be available before 2006," Professor Schmoll said.

Oncolytic Herpes simplex virus shows early promise against colorectal cancer

Tue, 07 Jun 2005 11:50:38 PST

( from http://www.rxpgnews.com ) A single injection of a genetically engineered virus has shown promise as a treatment for patients with colorectal cancer that has spread to the liver, according to preliminary results reported today at the 2nd ESMO Scientific & Educational Conference (ESEC) in Budapest, Hungary.

In their phase I study, Professor Nancy Kemeny from Memorial Sloan-Kettering Cancer Center in New York, and colleagues tested an oncolytic Herpes simplex virus (oHSV). These viruses selectively kill cancer cells while sparing normal tissue and are considered a promising new strategy to treat tumors. They have already been shown to be effective against chemotherapy-resistant cancers in preclinical studies.

The specific strain of virus investigated by Prof. Kemeny's team was NV1020, weakened and altered form of herpes simplex virus type-1, the virus associated with cold sores.

In 12 patients with colorectal adenocarcinoma that had spread to the liver and proven resistant to first-line chemotherapy, the scientists tested increasing doses of NV1020 delivered via a single 10-minute arterial infusion. Treatment was followed by regional chemotherapy.

Patients in the study generally experienced mild or moderate adverse events associated with the treatment, the researchers found, although self-limiting serious adverse events experienced by three patients were considered possibly or probably related to NV1020. These events comprised a temporary increase of gamma-glutamyl transpeptidase--a sign of liver disease--12 hours after treatment in a patient with a history of hepatitis, a case of gastroenteritis, and a case of mild leukocytosis considered due to a respiratory infection.

None of the patients showed any signs of disseminated herpes infection; the virus was detected in just one saliva sample and two blood samples from one asymptomatic patient who received the highest dose.

"Our primary aim in this study was to test the safety of the virus," Professor Kemeny said. "We were pleased to see that the virus could be administered safely in the hepatic artery without significant effects on the normal liver function. We were also excited that CEA reductions were seen in patients after virus administration and before regional therapy."

So far, the overall median survival time of the 12 patients is 23 months with one patient still alive at 30 months post therapy.

"These results are very promising," Professor Kemeny says. "The median survival time we saw among our patients was higher than you might expect among this group of patients. However, all were treated with hepatic arterial therapy and systemic therapy after the virus therapy."

The next step for the investigators is to use multiple doses of the virus since there are preclinical data to indicate that herpes oncolytic viruses work best when administered in multiple doses.

Commenting on the report, Professor Hans Joachim Schmoll, of Martin-Luther-Universität Halle-Wittenberg in Germany, noted that locoregional chemotherapy is an excellent approach for delivering active drugs in metastatic colorectal cancer with liver metastases. "The application of the tumoricidal virus by the arterial route could be of high interest since higher viral load will be delivered to the liver metastases," he said.

"These results represent the first time that an anti-tumor response has been seen after intra-arterial or systemic application of a tumor killing virus", he added. "Therefore, the study is highly interesting and promising in terms of giving the basis for further trials with genetic-modified tumoricidal viral constructs."

Increased Vitamin B consumption reduces risk of colorectal cancer

Sat, 04 Jun 2005 02:04:38 PST

( from http://www.rxpgnews.com ) According to a study published in the American Gastroenterological Association (AGA) journal Gastroenterology, women with a high dietary intake of vitamin B6 over several years have a decreased risk of colorectal cancer (CRC). Women who consume moderate to large amounts of alcohol in addition to vitamin B6 have more than a 70 percent reduced risk of developing CRC.

"Consuming a diet high in vitamin B6 may reduce the risk of colorectal cancer in women, more specifically those who consume alcohol," said Susanna Larsson, MSc, study author with the Karolinska Institutet. "Inadequate vitamin B6 status may lead to the development of cancerous polyps in the colon, so it is important for women to maintain a normal to high intake of vitamin B6."

The second-leading cause of cancer deaths in the United States, it is estimated that more than 28,000 women with CRC will die in 2005. While increased vitamin B6 consumption decreases the risk of colorectal cancer, it does not eliminate the need for regular screening. Guidelines of multiple agencies and professional societies underscore the importance of colorectal cancer screening for all individuals 50 years of age and older.

Researchers at the Karolinska Institutet in Stockholm, Sweden and the Harvard School of Public Health used data from the Swedish Mammography Cohort to evaluate the association between long-term dietary vitamin B6 intake from food sources and colorectal cancer risk, and its modification by alcohol consumption. Nearly 67,000 women, aged 40 to 75 years, responded to a questionnaire that solicited data on diet, family history of CRC and use of dietary supplements. Researchers observed that alcohol consumption in women with low vitamin B6 intake resulted in higher risk of developing colorectal cancer and that increasing intake reduces this risk significantly.

The recommended daily dietary intake of vitamin B6 for non-pregnant women in the United States is 1.3 to 1.5 mg. Vitamin B6 is found in a wide variety of foods, including fortified cereals, beans, meat, poultry, fish, and some fruits and vegetables. It performs a wide variety of functions in the body, including helping to maintain normal blood glucose levels, fighting off infections and creating hemoglobin to ensure that oxygen gets to important organs and tissues.

While the study shows that consuming high amounts of vitamin B6 reduces the risk of colorectal cancer in women who drink, researchers say findings need further confirmation in large prospective cohort or intervention studies.

"These findings may have important implications for the prevention of colorectal cancer in women who consume alcohol because their vitamin B6 status can be easily improved through dietary modifications, vitamin supplementation and fortification," said Larsson.

More Data Support Panitumumab's Role in Metastatic Colorectal Cancer

Tue, 17 May 2005 19:12:38 PST

( from http://www.rxpgnews.com ) Amgen Inc. (NASDAQ:AMGN), the world's largest biotechnology company, and Abgenix, Inc. (NASDAQ:ABGX), a leading antibody development company, today announced updated results from an ongoing Phase 2 study of panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr).

The results demonstrate that panitumumab has antitumor activity when administered as a single-agent treatment to patients with metastatic colorectal cancer (mCRC) who have failed standard chemotherapy. An independent central radiology review determined that treatment with panitumumab resulted in a nine percent overall response rate and median time to progression of 11.4 weeks. (Abstract #3520)

The data were presented today at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). Investigators reported that patients with mCRC tumors expressing the EGFr protein who received panitumumab monotherapy demonstrated a median survival time of 37.6 weeks and a median duration of tumor response of 18.1 weeks. Stabilization of disease was observed in 29 percent of patients (n=43). Median progression-free survival time was 13.6 weeks.

"These data confirm previously reported safety and response findings in patients with metastatic colorectal cancer who have previously failed multiple lines of chemotherapy," said Imtiaz A. Malik, M.D., professor of medicine, Loma Linda University Cancer Institute, Loma Linda, Calif. and one of the study's lead investigators. "Panitumumab's efficacy and safety data from Phase 1 and Phase 2 clinical trials to date suggest that panitumumab may provide an additional avenue for oncologists to manage the disease."

Patients in the study (n=148) were previously treated with 5FU (with or without leucovorin) and either irinotecan or oxaliplatin, or both. Patients received 2.5 mg/kg of panitumumab by weekly one-hour intravenous infusion without premedication. Tumor responses were confirmed no less than four weeks after the initial response was observed.

In this Phase 2 study, the most common side effect was skin toxicity (95 percent, 7 percent grade 3). Other side effects experienced by some patients were fatigue, nausea and mild diarrhea. One infusion reaction (grade 3) was reported per investigator assessment and the patient continued on full-dose panitumumab with pre-medication. There were no instances of anaphylaxis observed. In those patients tested who had a baseline and a post-baseline assessment (n=107), no human antihuman antibodies (HAHAs) formation was observed.

Phase 1 Open-Label Dose Escalation Trial Suggests Panitumumab May Provide for Flexible Dosing Schedules in Cancer Patients (Poster K4, Abstract #3059)

Additional data from a Phase 1 open-label dose escalation trial were presented by Louis M. Weiner, M.D., chairman, department of medical oncology, and vice president, translational research at Fox Chase Cancer Center, Philadelphia, Pa. Exposure and tolerability profiles were similar between weekly, every-other-week and every-three-week dosing schedules.

"We are very encouraged by the safety profile at various doses of this antibody in cancer patients and in different types of cancers. We look forward to the continued evaluation of panitumumab, a promising antibody cancer therapeutic," said Dr. Weiner.

Patients (n=96) were randomized to receive four infusions of panitumumab at different dose levels and schedules ranging from 0.01 to 5.0 mg/kg once per week, 6.0 mg/kg once every two weeks or 9.0 mg/kg once every three weeks administered by intravenous infusion with no premedication required.

For further information concerning ongoing clinical trials involving panitumumab please visit, http://www.amgentrials.com/.

About Colorectal Cancer

Colorectal cancer is the third most common cancer diagnosed in men and in women in the United States. The American Cancer Society estimates that about 104,950 new cases of colon cancer (48,290 men and 56,660 women) and 40,340 new cases of rectal cancer (25,530 men and 16,810 women) will be diagnosed in 2005.

About Panitumumab

Co-developed by Amgen and Abgenix, panitumumab is an investigational product in a novel class of targeted cancer treatments called epidermal growth factor receptor (EGFr) inhibitors. Panitumumab (formerly ABX-EGF) is the first fully human monoclonal antibody directed against EGFr and is being evaluated as both a monotherapy and in combination with other agents for the treatment of various types of cancer, including colorectal, lung and kidney. Panitumumab was generated with Abgenix's XenoMouse(R)(1) technology, which creates a fully human monoclonal antibody that contains no murine (mouse) protein.

The fully human nature of panitumumab may result in a safety profile with a low incidence of infusion reactions and antigenicity. These are attributes currently being investigated in clinical trials. Pivotal clinical studies evaluating panitumumab as a monotherapy in colorectal cancer patients who have failed standard chemotherapy are ongoing with an every-other-week dosing regimen.

About the Epidermal Growth Factor Receptor (EGFr)

Although EGFr normally helps regulate the growth of many different cells in the body, EGFr can also stimulate cancer cells to grow. In fact, many cancer cells actually require signals mediated by EGFr for their survival. Residing on the surface of these tumor cells, EGFr is activated when naturally occurring proteins in the body, epidermal growth factor (EGF) or transforming growth factor alpha (TGFa), bind to it. This binding changes the shape of EGFr, which, in turn, triggers internal cellular signals that stimulate tumor cell growth.

Panitumumab binds to EGFr, preventing EGF and TGFa from binding to the receptor and interfering with the signals that would otherwise stimulate growth of the cancer cell and allow it to survive.

Aspirin May Reduce Risk of Colon Cancer Recurrence

Tue, 17 May 2005 01:53:38 PST

( from http://www.rxpgnews.com ) Researchers from the Cancer and Leukemia Group B (CALGB), a national clinical research group in the United States, found that regular aspirin use among colon cancer patients following surgery reduced the risk of recurrence and death by approximately 50% compared with non-users.

The study, which was primarily designed to assess post-operative adjuvant chemotherapy in stage III colon cancer patients, also demonstrated a benefit to using aspirin in people who have already been diagnosed with colon cancer. A beneficial effect was also seen with celecoxib (Celebrex) and rofecoxib (Vioxx). No such benefit was found with regular acetaminophen use.

Previous studies in both animals and people have shown that regular aspirin use may reduce the risk of developing colon cancer and benign growths called polyps. Animal studies have also suggested that the benefits of aspirin may extend to people who already have colon cancer, by reducing their risk of recurrence.

Researchers prospectively studied 830 patients with stage III colon cancer undergoing post-operative adjuvant chemotherapy to analyze the relationship between aspirin and cancer recurrence. They also evaluated the relationship between cancer recurrence and selective cyclo-oxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib.
Participants completed surveys about their use of aspirin and other medications midway through therapy and six months after completion of treatment. Consistent aspirin use was reported by 8.7% of the patients (most of whom took 81 mg to 325 mg per day), while 4.3% of patients reported regular use of celecoxib or rofecoxib.

After a median of 2.4 years of follow-up, the risk of colon cancer recurrence was 55% lower and the risk of death was 48% lower among the aspirin users compared with non-users. Although no dose-response analysis was reported, the benefit of aspirin persisted independent of dose, as long as the patient consistently took aspirin throughout the follow-up period. Use of celecoxib or rofecoxib reduced the risk of recurrence by 44%.

"While aspirin appears to reduce the risk of cardiovascular disease, it may be premature to advise colorectal cancer patients to start taking aspirin regularly for the purpose of reducing their risk of recurrence," said Charles Fuchs, MD, MPH, Associate Professor of Medicine at the Dana-Farber Cancer Institute in Boston, and the study's lead author. "More studies are clearly needed to confirm our findings. People with colon cancer who are interested in taking aspirin should first speak with their doctors." Dr. Fuchs added that another study evaluating the use of celecoxib in patients with colon cancer is ongoing.

Keyhole Surgery Set to become Gold Standard in Colon Cancer

Fri, 13 May 2005 21:47:38 PST

( from http://www.rxpgnews.com ) Keyhole surgery for colon cancer is as effective as open surgery in the short term, concludes a randomised trial published in this weeks issue of The Lancet.

Treatment for colon cancer involves surgical excision of the primary tumour. Keyhole surgery may lead to a more rapid recovery, less pain, fewer complications and a shorter hospital stay. However, it has been widely adopted for colorectal cancer without data from large clinical trials to support its use.

Pierre Guillou (St. Jamess University Hospital, Leeds, UK) and colleagues undertook a trial to compare keyhole surgery with open surgery, involving around 730 colorectal cancer patients, from 27 centres around the UK. 253 patients received open surgery and 484 received keyhole surgery. 143 patients underwent conversion from keyhole surgery to open surgery. Based on detailed pathological examination of the resected bowel, which contained the tumour, the investigators found that local recurrence rates were unlikely to be higher for keyhole surgery than for local surgery. They also found that cancer-related survival and quality of life was similar for the two groups. Conversions from keyhole to open surgery were more common in patients with cancer of the rectum; and individuals who had their operation converted had the most complications from surgery.

Professor Guillou concludes: For cancer of the colon, little difference seems to exist between keyhole surgery and open surgery and there is no reason to expect long-term cancer outcomes to be different. However, impaired short-term outcomes after keyhole surgery for rectal cancer do not yet justify its routine use.

In an accompanying Comment Myriam J Curet (Stanford University, California, USA) states: Keyhole surgery for colon cancer has not been adopted as quickly by the surgical community as other keyhole procedures. In part, the technical challenges of the operation have prolonged the learning curve and minimised enthusiasm. In addition, major concerns about the oncological effects of the operation in patients whose disease has spread have limited its application in colorectal cancer. However, this trial suggests that in appropriately selected patients who are operated on by experienced surgeons, keyhole surgery for colorectal cancer may be the new gold standard.

Check Colon Tumors for Signs of Syndrome - Study

Sat, 07 May 2005 18:50:38 PST

( from http://www.rxpgnews.com ) A new study suggests that, after surgery, all colon tumors should be tested to learn if the patient may have an inherited syndrome that carries an extremely high risk of cancer. It also suggests that this prescreening can be done using a relatively inexpensive microscopy test already used in hospital pathology laboratories.

The study showed that two to three percent(at least one in 45) of people with colon cancer probably have mutations for the inherited syndrome, known as Lynch syndrome (also known as hereditary nonpolyposis colon cancer, or HNPCC).

Prescreening for Lynch syndrome will help determine if the person and his or her relatives should consider genetic counseling and testing for the syndrome. In addition, the test might help doctors better estimate a patient's long-term prognosis.

The study, led by researchers with The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, is published in the May 5 issue of the New England Journal of Medicine.

Lynch syndrome is caused by a mutation in one of four genes. One out of two first-degree relatives of those with the syndrome are also likely to have the mutations.
It's important that people who have this syndrome know they have it because there is a good chance we can prevent cancer from developing or at least detect it early when it is more easily treated.

These are particularly bad mutations, says principal investigator Albert de la Chapelle, professor of molecular virology, immunology and medical genetics at Ohio State . A person who has one of these mutations has an almost 100 percent lifetime risk of cancer.

The risk is highest for colon cancer, followed by a lower risk of uterine cancer and several other cancers, he says.

People with Lynch syndrome need closer cancer surveillance, with annual colonoscopies starting at age 25, de la Chapelle says. This has been proven to prevent cancer and to prevent death from cancer.

In addition, he says, it is important for someone in a high-risk family to know that he or she lacks the mutation. Those relatives do not require the intense cancer surveillance.

Lynch-syndrome mutations occur in about one person per thousand of the general population.

The study led by de la Chapelle involved 1,066 patients with newly diagnosed colorectal cancer from six hospitals in the Columbus, OH, metropolitan area. Tumor cells from each patient were tested for microsatellite instability (MSI), a hallmark of Lynch syndrome. MSI occurs in more than 90 percent of Lynch syndrome tumors.

To learn the frequency of Lynch syndrome generally, the researchers tested all the tumors for the presence of MSI. They also used an alternative method to prescreen for mutations known as immunohistochemistry. Of the 1,066 tumors tested, 208 showed MSI. Of these, 23 (2.2 percent of the total) had Lynch syndrome mutations. Five of the tumors came from patients that did not meet the usual criteria for diagnosing Lynch syndrome. That diagnosis is largely based on family history and age. Ordinarily, these five cases would have gone undiagnosed.

Furthermore, the 23 people with Lynch syndrome had 117 first-degree relatives who also may have inherited the mutations. The counseling and testing of these individuals revealed 52 people with undiagnosed Lynch syndrome; 65 of the people had no mutations.

There are now 52 people who know they have Lynch syndrome because they had a relative in this study, says first author Heather Hampel, a genetic counselor with The James Cancer Hospital and Solove Research Institute.

It's important that people who have this syndrome know they have it because there is a good chance we can prevent cancer from developing or at least detect it early when it is more easily treated.

The study also identified immunohistochemistry as an effective way to prescreen colon tumors for MSI, suggesting that Lynch syndrome mutations may be present. The method is less costly than the usual means of identifying MSI, a method known as genotyping, and it can be done by most hospital pathology laboratories. As the next step before proposing nation-wide screening for Lynch syndrome the OSU researchers are planning to implement their screening strategy Ohio-wide.

Testing all colon tumors for MSI is becoming important because patients with tumors that show MSI tend to have a better prognosis than patients whose tumors do not.

So using this test to prescreen for Lynch syndrome should also help oncologists give patients more accurate information about their prognosis and five-year survival, Hampel says.

Vitamin B6 May Reduce Risk of Colorectal Tumors

Wed, 04 May 2005 17:25:38 PST

( from http://www.rxpgnews.com ) Vitamin B6 intake may be associated with lower future risk of colorectal tumors in women, according to a new study.

Several nutrients, including vitamin B6, play important roles in biochemical pathways related to DNA synthesis and DNA methylation, which are involved in carcinogenesis. Esther K. Wei, Sc.D., from Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues studied whether vitamin B6 measured as dietary intake and as the main active circulating form, known as pyridoxal 5'-phosphate, or PLP, is associated with the risk of colorectal cancer and colorectal adenoma in women by performing a nested casecontrol study of 32,826 women in the Nurses' Health Study who provided blood specimens between 1989 and 1990.

During the study period, 194 colorectal cancer cases and 410 colorectal adenoma cases were identified. The authors observed that women in the highest quartile of plasma PLP concentration, compared with women in the lowest quartile, had a reduced future risk of colorectal cancer and colon cancer, after adjusting for important risk factors associated with colorectal cancer as well as dietary folate and methionine intake, and multivitamin use. Total vitamin B6 intake was also inversely associated with future risk of colorectal tumors among these women. "Additional animal, epidemiologic, and intervention studies are required to clarify the association between dietary and plasma vitamin B6 and colorectal neoplasia," the authors write.

Phase III Trail to Study Benefits of Panitumumab in Chemotherapy Regimens for Metastatic Colorectal Cancer

Wed, 27 Apr 2005 09:10:38 PST

( from http://www.rxpgnews.com ) Amgen Inc. (Nasdaq: AMGN - News) and Abgenix, Inc. (Nasdaq: ABGX - News) today announced the initiation of a Phase 3 clinical study to evaluate the potential benefits of adding panitumumab, an experimental fully human monoclonal antibody, administered every other week to bevacizumab (Avastin(TM), Genentech) and either oxaliplatin- (Eloxatin®, sanofi-aventis) or irinotecan-based (Camptosar®, Pfizer) chemotherapy for the first-line treatment of metastatic colorectal cancer.

The clinical trial, called the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) study, is a randomized, multi-center, open-label study, with endpoints of progression free survival, overall survival and response rate. Enrollment in the study of approximately 1,000 patients is already underway.

"Targeting multiple pathways that aid in tumor survival and growth at the same time or in succession theoretically has advantages over targeting one pathway alone," said Willard Dere, M.D., chief medical officer and senior vice president of global development at Amgen. "In clinical studies to date, panitumumab appears to be well tolerated, and interim Phase 2 data demonstrate that objective tumor responses in metastatic colon cancer patients occurred following panitumumab treatment."

"We are delighted with the initiation of this important clinical trial to further explore the potential for our lead product, panitumumab, in the first-line treatment of metastatic colorectal cancer," said Bill Ringo, president and chief executive officer at Abgenix. "This study is a key step in the overall clinical program for panitumumab, which we expect to be evaluated with various chemotherapy agents and targeted therapies across multiple tumor types."

Panitumumab inhibits the epidermal growth factor receptor (EGFr), while bevacizumab targets the vascular endothelial growth factor involved in angiogenesis. Although EGFr normally helps regulate the growth of many different cells in the body, EGFr can also stimulate cancer cells to grow. In fact, many cancer cells actually require signals mediated by EGFr for their survival.

Residing on the surface of these tumor cells, EGFr is activated when naturally occurring proteins in the body, epidermal growth factor (EGF) or transforming growth factor alpha (TGF alpha), bind to it. This binding changes the shape of EGFr, which, in turn, triggers internal cellular signals that stimulate tumor cell growth.

Panitumumab binds to EGFr, preventing EGF and TGF alpha from binding to the receptor and interfering with the signals that would otherwise stimulate growth of the cancer cell and allow it to survive.

Patients and physicians can access www.amgentrials.com for more information about ongoing panitumumab clinical trials.

About Panitumumab

Co-developed by Amgen and Abgenix, panitumumab is an investigational product in a novel class of targeted cancer treatments called epidermal growth factor receptor (EGFr) inhibitors.

Panitumumab (formerly ABX-EGF) is the first fully human monoclonal antibody directed against EGFr and is being evaluated as both a monotherapy and in combination with other agents for the treatment of various types of cancer, including colorectal, lung and kidney. Panitumumab is generated with Abgenix's XenoMouse® technology, which creates a fully human monoclonal antibody that contains no murine (mouse) protein.

The fully human nature of panitumumab may result in a favorable safety profile with a low incidence of infusion reactions, antigenicity and allergic response. These are attributes currently being investigated in clinical trials. Pivotal clinical studies evaluating panitumumab as a third-line monotherapy in colorectal cancer patients are ongoing with an every-other-week dosing regimen.

Major Colorectal Cancer Screening Study Enters Last Phase of Recruitment

Wed, 20 Apr 2005 19:45:38 PST

( from http://www.rxpgnews.com ) Having recently enrolled the 4,000th study participant, researchers want to emphasize that there is still an opportunity for an additional 400 people to participate in this trial before recruitment stops at the end of May.

Mayo Clinic continues to successfully enroll men and women in a large colorectal screening clinical trial. Mayo is the lead medical center and is one of 34 sites in the United States that is participating in this research project.

Launched in October 2001 and sponsored by the National Cancer Institute (NCI), this research study seeks to enroll healthy men and women between the ages of 65 and 80 who have not been screened for colorectal cancer within the past 10 years. This trial is attempting to compare a non invasive DNA-based stool test against colonoscopy, which is the accepted standard for colorectal cancer screening.

Colorectal cancer is one of the most common cancers in the United States, affecting one in every 17 persons. Death rates from colorectal cancer are second only to lung cancer deaths in the United States. It occurs with equal frequency in men and women and is most often found among people who are over age 50.
The toll in terms of suffering, lost productivity, and cost is enormous but colorectal cancer is preventable with screening.

Multiple medical societies, including the American Cancer Society, recommend regular screening after age 50, but less than one-third of Americans have ever been screened. Barriers to screening have included lack of awareness, inconsistent insurance coverage by third parties, and patient fear or non acceptance of the screening intervention.

"In our study, funded by the National Cancer Institute, we are evaluating a promising new DNA-based stool test that requires no bowel preparation or diet restriction," said David Ahlquist, M.D., a Mayo gastroenterologist and the national study chair. "This study will provide important data on the performance of this new test and will allow us to determine its value as a potential screening method."

Organochlorines in Diet increase risk of Colon Cancer

Sun, 03 Apr 2005 11:35:38 PST

( from http://www.rxpgnews.com ) A team of researchers at the Universitat Autònoma de Barcelona, The Catalan Institute of Oncology and the Higher Council for Scientific Research (CSIC) have published a study indicating that exposure to organochlorine compounds, which we ingest in our diets, increases the risk of suffering colorectal cancer. The authors have identified two types of compounds, present in the blood of cancer patients, in double the quantity of the non-affected population undergoing the study. In addition, the researchers studied the mechanism that triggers the disease. They have been able to deduce that these compounds cause genetic alterations in genes such as the K-Ras and the p53, which are involved in other cancers such as breast cancer or cancer of the pancreas.

Colorectal cancer is the third most frequent type of cancer in humans and the second deadliest in industrialised countries. Its causes, however, are not fully understood, but diet is believed to play an important role. It is thought that vegetables, fruit and fibre-rich foods protect against it; fats, red meat, as well as excessive consumption of calories, and obesity increase the risk of developing it.

To better understand the causes, a team of researchers led by Victor Moreno, researcher at the Universitat Autònoma de Barcelona and The Catalan Institute of Oncology, in collaboration with the CSIC's Environmental Chemistry Group, have published the first work that establishes an association between organochlorine compounds and colorectal cancer. The article has been published in the specialised journal, Environmental Health Perspectives.

The researchers measured the concentration of organochlorines in the blood serum of a group of patients at the Bellvitge Hospital. One hundred and thirty-two of the patients had been diagnosed with the disease and 76 others were admitted for other reasons. The analyses identified two specific organochlorines: PCB 28 and PCB 118, which were found at a concentration double that found in the remaining patients. These substances belong to the PCBs or polychlorinated biphenyls. They are toxic compounds coming from industrial processes, which are absorbed into the body through what we eat.

At the same time, the team studied patients affected by colon cancer and two genes implicated in the cancer's development: the K-Ras oncogene and the P53 tumour suppressing gene. The study of mutations indicated the relationship between exposure to PCBs and the presence of transversion type mutations in both genes. That result reinforces the role of PCBs 18 and 128 as probable causes of the carcinogenic processes in the population studied.

The authors believe that the two compounds' ability to produce mutations lies in their unique shape. They have a flat conformation similar to that of the dioxins, which allows them to initiate a chain of chemical processes that can end in a carcinogenic process. An example of this would be the bonding of the compounds to the aryl hydrocarbon receptor that due to their shape would set off the activation of cellular enzymes that produce reactive oxygen species. The latter are precisely what cause damage to the DNA thereby initiating the carcinogenic process.

In addition, the researchers studied other variables such as food intake to discover whether other factors were involved in increasing the risk. Nevertheless, the results were negative for all groups of foods and only alcohol was seen to be an important risk factor for the population under study.

According to the authors, further studies will need to be done in the future to confirm the results. Those studies would benefit from the inclusion of additional organochlorines, which were not analysed this time, as well as by the inclusion of other compounds associated with cancer such as dioxins and furans.

Capecitabine : An Innovative Oral Chemotherapy Provides an Effective, Convenient Alternative for Colon Cancer Patients

Sun, 03 Apr 2005 10:13:38 PST

( from http://www.rxpgnews.com ) Roche announced today that the European authorities have approved Xeloda ( capecitabine ), an innovative oral chemotherapy, to be used as an adjuvant treatment ( post-surgery ) for colon cancer.

Patients will now have the choice of an effective, convenient chemotherapy that prolongs cancer free life, with a less serious side effect profile compared to the current standard treatment of intravenous 5-Fluorouracil/ leucovorin ( i.v. 5-FU/LV ).

Adjuvant chemotherapy is the standard treatment approach for stage III colon cancer where chemotherapy is given in order to destroy any cancerous cells remaining in the body after the tumour has been surgically removed.

The European approval for Xeloda's new indication, again confirms Roche's commitment to providing innovative solutions for patients, whilst providing medical resource cost savings for today's healthcare providers said William M. Burns, CEO of Roche's Pharmaceutical Division. For the first time colon cancer patients will have access to a unique treatment option that provides an effective oral therapy which is well-tolerated and can be taken at home.

As the European approval decision was based on the landmark X-ACT trial, which showed that Xeloda should replace standard intravenous chemotherapy 5FU/LV, physicians and patients can be fully confident that they are using a very effective, safe and convenient treatment that is now available. said Professor Jim Cassidy, Cancer Research UK Professor of Oncology and Chair of Medical Oncology, Beatson Oncology Centre, at the University of Glasgow in Scotland.

The landmark X-ACT ( Xeloda in Adjuvant Colon Cancer Therapy ) trial which successfully met its primary endpoint, demonstrated that Xeloda is at least as effective compared to intravenous 5-FU/LV in terms of disease-free survival with a superior reduction in the risk of cancer recurrence ( relapse-free survival ).

In addition, on average, a patient only needed 8 hospital visits when treated with Xeloda compared to 30 visits if treated with i.v. 5-FU/LV. This results in significant cost savings, an important advantage for doctors, nurses and pharmacists in today's healthcare environment.

In 2004 approximately 88,000 patients in Europe who had advanced colorectal or breast cancer benefited from Xeloda. Based on the new indication approximately 55,000 colon cancer patients a year can now also be treated with this effective and convenient oral cancer treatment. Global sales in 2004 were 534 million Swiss francs and are expected to accelerate in 2005.

For African Americans Colo-Rectal Screening should begin at 45

Mon, 21 Mar 2005 18:08:38 PST

( from http://www.rxpgnews.com ) Physician experts from the American College of Gastroenterology have issued new recommendations to healthcare providers to begin colorectal cancer screening in African Americans at age 45 rather than 50 years. Colonoscopy is the preferred method of screening for colorectal cancer and data support the recommendation that African-Americans begin screening at a younger age because of the high incidence of colorectal cancer and a greater prevalence of proximal or right-sided polyps and cancerous lesions in this population.

The recommendations are published in the March issue of the American Journal of Gastroenterology. Overall, colorectal cancer is the second leading cause of cancer deaths in the United States. African Americans are diagnosed with colorectal cancer at a younger age than whites, and African Americans with colorectal cancer have decreased survival compared with whites. The article reviews the evidence why African Americans should have their colons screened for cancer at age 45 instead of age 50, five years earlier than the current recommendations. The article was drafted by the American College of Gastroenterology's Committee on Minority Affairs and Cultural Diversity.

The Committee recommends colonoscopy as a "first line" screening procedure for colorectal cancer for African Americans rather than flexible sigmoidoscopy because of the high overall risk and as well as some evidence that African Americans have more right-sided cancers and polyps. The right side of the colon includes the cecum, ascending colon and proximal transverse colon and cannot be reached by flexible sigmoidoscopy.

Clinical gastroenterologists play an important role in promoting colorectal cancer awareness and the need for screening in African Americans. Evidence suggests African Americans are more responsive to screening recommendations from their personal physicians than from other sources. The College urges physicians to provide culturally sensitive patient education on colorectal cancer to African Americans.

Reducing the high morbidity and mortality associated with colorectal cancer among African Americans continues to be a major healthcare challenge in the United States. In response to this challenge, the leadership of the American College of Gastroenterology asked the Committee on Minority Affairs and Cultural Diversity to develop a position paper on colorectal cancer in African Americans. The committee has done an extensive review of the literature on colorectal cancer screening and issues related to screening in African Americans to support their recommendations. One important goal was to improve awareness among primary care physicians and gastroenterologists of the important differences in colorectal cancer between African Americans and Caucasians.

PTK/ZK CONFIRM 1 Study Shows Positive Drug Effects in Phase III Study in Metastatic Colorectal Cancer

Mon, 21 Mar 2005 15:17:38 PST

( from http://www.rxpgnews.com ) Novartis Pharma AG and Schering AG announced today that the analysis of progression free survival (PFS) as assessed by central radiology review in the CONFIRM 1 trial with the investigational drug PTK/ZK did not achieve statistical significance. However, a separate pre-planned analysis of progression-free survival as assessed by the investigators achieved statistical significance.

Further analysis of the data including more detailed evaluations of subpopulations are ongoing to fully assess the potential benefit of PTK/ZK. In the study, PTK/ZK was given in combination with the chemotherapy regimen oxaliplatin/5FU/LV, called FOLFOX-4, compared with FOLFOX-4 alone in previously untreated patients.

Based on a review of the CONFIRM 1 results, an independent data monitoring board recommended the Phase III clinical trial program to continue to allow analysis of overall survival endpoints. This is expected in 2nd half of 2006.

Another ongoing phase III trial, CONFIRM 2, compares the PTK/ZK combination regimen to FOLFOX-4 alone in patients with metastatic colorectal cancer who have progressed after irinotecan-based chemotherapy. An interim analysis is planned in mid- 2005 and final overall survival data are expected in mid-2006.

Novartis and Schering now anticipate filing for approval with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) in early 2007. The CONFIRM 1 data will be submitted as a late-breaking abstract to the American Society of Clinical Oncology (ASCO) meeting in Orlando, Florida, May 13-17, 2005.

"The recommendation by the independent monitoring board to continue the Phase III program, and the investigator assessment of progression encourage us to further explore the potential benefit of PTK/ZK in patients suffering from metastatic colorectal cancer and other cancers," said David Epstein, CEO of Specialty Medicines and president of Novartis Oncology. "Novartis and Schering look forward to the complete data analysis of the ongoing Phase III program."

Aspirin's ability to prevent colon polyps may not apply equally to all

Fri, 18 Mar 2005 23:23:38 PST

( from http://www.rxpgnews.com ) The association between regular aspirin use and a reduced risk of precancerous colon polyps may be strongest in those with particular genetic variants. In the March 16 Journal of the National Cancer Institute, researchers report that aspirin use appears to reduce the incidence of colon polyps more strongly in women with alternative forms of a gene involved in the metabolism of aspirin than in those with the most common form of the gene. The report from researchers at Massachusetts General Hospital (MGH), Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute (DFCI) analyzes data from the Nurse's Health Study.

"Several studies by our group and others have suggested that aspirin may help prevent colon polyps, but since aspirin therapy also has risks, it would be helpful to identify those who are most likely to benefit," says Andrew T. Chan, MD, MPH, of the MGH Gastrointestinal Unit, the paper's lead author. "We decided to look at the gene for an enzyme that metabolizes aspirin and is known to have variant forms that slow down that process."

The Nurses' Health Study has followed more than 120,000 female registered nurses since the mid-1970s, asking them to complete a questionnaire on risk factors for cancer and cardiovascular disease every two years. In 1980, assessments of diet, aspirin use, and colon examination were added to the NHS questionnaire, and in 1990 many participants provided blood samples that could be analyzed for genetic factors.

The current study analyzed the blood samples from participants who reported having endoscopic colon examinations between 1990 and 1998. About 500 of those participants had been diagnosed with adenoma a type of colorectal polyp that may develop into cancer and their data was compared with a control group consisting of an equal number of women not diagnosed with polyps.

While the incidence of polyps was significantly lower in those who took aspirin regularly defined as two or more tablets per week that benefit was primarily seen in participants with variant forms of the enzyme known as UGT1A6. Among participants with the most common form of the enzyme, the improvement in risk was not statistically significant. As in previous studies, the higher the intake of aspirin, the greater the risk reduction, but again that improvement was strongest in those with the altered form of the enzyme.

"These altered genes slow the metabolism of aspirin so it may linger in the body longer. This could explain why aspirin may have a stronger effect in preventing polyps for these slow-metabolizers," says Chan. "But the persistence of aspirin in the body could also increase the risk for side effects like bleeding.

Until we can get a more complete picture of the risks and benefits, which will require larger studies, we can't make any definitive recommendations about preventive aspirin therapy." Chan is an instructor in Medicine at Harvard Medical School.

Antioxidant blood levels key to MnSOD gene

Fri, 18 Mar 2005 23:23:38 PST

( from http://www.rxpgnews.com ) Greater levels of selenium, vitamin E and the tomato nutrient lycopene have been shown to reduce prostate cancer in one out of every four Caucasian males -- those who inherit a specific genetic variation that's particularly sensitive to oxidative stress.

Conversely, if carriers of this genetic variant have low levels of these vitamins and minerals, their risk of aggressive prostate increases substantially, as great as 10-fold, over their cohorts who maintain higher levels of these nutrients.

These results, published in the March 15 issue of the journal Cancer Research, were based on the analysis of 567 men diagnosed with prostate cancer between 1982 and 1995, and 764 cancer-free men from the Physicians Health Study (PHS).

"This large prospective study provides further evidence that oxidative stress may be one of the important mechanisms for prostate cancer development and progression, and adequate intake of antioxidants, such as selenium, lycopene and vitamin E, may help prevent prostate cancer," said Haojie Li, M.D., Ph.D., a researcher at the Brigham and Women's Hospital and Harvard Medical School.

Destructive molecules known as "free radicals" have been shown to team up with oxygen in the human body resulting in oxidative stress and what some scientists believe is an assortment of age-related ailments. As a result, many believe that consumption of antioxidants can slow that process.

"Our study, as well as many other epidemiological studies, encourages dietary intake of nutrients such as lycopene from tomato products, or supplements for vitamin E and selenium to reduce risk of prostate cancer," said Li.

The initial goal of the PHS study was to assess the effect of aspirin and beta carotene on men's health. Since blood samples collected in 1982 were available from many of the study's participants, the research team decided to review variants for the gene that codes for manganese superoxide dismutatase (MnSOD), an important enzyme that works as an antioxidant in human cells to defend against disease. The MnSOD gene is passed from parents to offspring in one of three forms: VV, VA or AA.

"Compared with men with the MnSOD VV or VA genotype, people with the AA genotype seem to be more sensitive to the antioxidant status," said Li. "Men with the AA genotype are more susceptible to prostate cancer if their antioxidant levels are low."

The study's results found that a quarter of the men in the study carried the MnSOD AA genotype, half carried the VA genotype, and the remaining quarter carried the VV genotype.

The results indicated that the VA and VV men were at equivalent risk for developing prostate cancer across all levels of antioxidants in their blood. Compared to MnSOD VV or VA carriers with low selenium those men in the lowest quartile of the study group MnSOD AA males had an 89 percent greater risk for developing aggressive prostate cancer if blood levels for selenium were low.

On the other hand, MnSOD AA carriers with high selenium those men in the highest quartile had a 65 percent lower risk than the MnSOD VV or VA males who maintained low levels of selenium.

"The levels of selenium in the highest quartile of these men are not abnormally high," Li said. "Our range is neither extremely high nor extremely low."

While similar trends were observed for lycopene and vitamin E when tested independently, the contrast in relative risk was most pronounced for the men who had high blood levels for all three antioxidants combined.

"Among men with the MnSOD AA genotype, we observed a 10-fold difference in risk for aggressive prostate cancer, when comparing men with high versus low levels of antioxidants combined," said Li. "In contrast, among men with the VV or VA genotype, the prostate cancer risk was only weakly altered by these antioxidant levels."

Similar interactions between dietary antioxidants and the variations in the MnSOD gene have previously been linked to risk for breast cancer.

Variant Polymorphism May Affect Aspirin Chemoprevention of Colorectal Cancer

Fri, 18 Mar 2005 23:17:38 PST

( from http://www.rxpgnews.com ) A new study has found that, among women with a common variant polymorphism that affects an enzyme that metabolizes aspirin, regular aspirin use is associated with a decreased risk of colorectal adenoma. But regular aspirin use is not associated with the same reduction in risk of colorectal adenoma among women who have a normal form of the enzyme.

Regular aspirin use has been associated with an overall reduced risk of colorectal adenoma. More rapid aspirin metabolism may decrease the therapeutic effect of aspirin. Consequently, polymorphisms in the enzyme UGT1A6, which metabolizes aspirin, may modulate the protective benefit of aspirin.

To determine whether polymorphisms in UGT1A6 are associated with colorectal adenoma risk, Andrew T. Chan, M.D., M.P.H., of Massachusetts General Hospital in Boston, and colleagues conducted a nested casecontrol study of 1,062 women participating in the Nurses' Health Study. They found that among the women with variant polymorphisms, regular aspirin use was associated with a decreased risk of adenoma, and the risk decreased further with higher doses of aspirin. However, among the women the normal form of the enzyme, regular aspirin use was not associated with a reduced risk, and these women did not benefit from higher aspirin doses.

Prostate screenings could be 'teachable moment' to encourage colon checks

Thu, 03 Mar 2005 17:11:38 PST

( from http://www.rxpgnews.com ) Colon cancer is the third leading cause of cancer death in men, but according to a new University of Michigan Health System study, fewer than half of men surveyed were up-to-date with colon cancer screenings.

What men do pay attention to is prostate cancer. And that has researchers thinking an annual prostate cancer screening might be a good opportunity to urge men to be screened for colon cancer too.

Researchers looked at 22,617 men age 50 and older who had responded to the 2002 Behavioral Risk Factors Surveillance Survey, an annual phone survey of adults that measures preventive health behaviors. The study found that while nearly two-thirds of men were up-to-date with prostate cancer screening, only 47.6 percent had had a recent colon cancer screening.

More than 70,000 men will be diagnosed with colorectal cancer this year, according to the American Cancer Society; some 28,000 will die from the disease. Experts recommend people age 50 and older get a fecal occult blood test annually, sigmoidoscopy every five years or colonoscopy every 10 years. These tests are highly effective at catching the disease early and reducing deaths.

The screening test for prostate cancer, called the prostate specific antigen, or PSA, test, is more controversial. Experts continue to debate what PSA level is cause for follow-up, and research suggests the test has not led to fewer deaths from prostate cancer.

"Colon cancer screening is proven to be effective at reducing deaths from colon cancer, while the effectiveness of the PSA test in reducing mortality continues to be debated. If we can turn the PSA test into an opportunity to encourage men to get their colons checked too, it would take advantage of the public demand for PSA testing," says lead study author Ruth Carlos, M.D., assistant professor of radiology at the University of Michigan Medical School.

In the study, which appears in the February Journal of the American College of Surgeons, researchers found men who adhered to colon cancer screening guidelines tended to be older and had a higher income level and more education than men who did not follow screening guidelines. One-third of men who said they regularly have the PSA test were not up-to-date with their colon cancer screening.

Carlos has previously looked at women's adherence to colorectal cancer screenings and compared it to mammograms to screen for breast cancer and Pap smears to check for cervical cancer. That research found only half of women who got regular mammograms and Pap smears also had a colonoscopy or other colon cancer screening.

Carlos is currently leading a clinical trial that randomizes women to receive education during their mammogram appointments about either colorectal cancer screening or diabetes screening. The researchers will review the women's records up to a year later to see if they get checked for colon cancer or spoke to their physicians about it.

If successful, Carlos says, the same approach could be taken for men during prostate cancer screenings.

"Men are already paying attention to their cancer risk in one area. If we can take advantage of that consciousness to educate them about another cancer risk, it might lead to more early detection of colorectal cancer," Carlos says. Research has shown these "teachable moments" are more effective than untimed formal interventions at changing health behavior.

The researchers also suggest targeting information on colon cancer to the type of patient less likely to be screened for the disease. The study found men who were not compliant were younger, were Hispanic, had lower education and income levels, and were smokers. Outreach efforts could focus on predominantly Hispanic neighborhoods or be combined with smoking cessation programs, for example.

Role of IGF2 in Colon Cancer

Fri, 25 Feb 2005 18:38:38 PST

( from http://www.rxpgnews.com ) A team of scientists from the United States, Sweden and Japan has discovered that in mice having a double dose of one protein is sufficient to change the normal balance of cells within the lining of the colon, thereby doubling the risk that a cancer-causing genetic mutation will trigger a tumor there. Roughly 10 percent of people have this double protein dose as well.

In the Feb. 24 online version of Science, the researchers report that mice engineered to have a double dose of insulin-like growth factor 2 (IGF2) develop more so-called precursor cells within the lining of the colon than normal mice. When these mice also carried a colon-cancer-causing genetic mutation, they developed twice as many tumors as those with normal IGF2 levels, the researchers report.

"Both clinically and scientifically, this discovery should expand attention in colon cancer research to earlier events, situations present well before tumors appear," says the study's leader, Andrew Feinberg, M.D., M.P.H., professor of medicine and director of the Center for Epigenetics in Common Human Disease at Johns Hopkins.

"In the mice with a double dose of IGF2, everything is pretty normal except for the extra precursor cells," says Christine Iacobuzio-Donahue, M.D., assistant professor of pathology and oncology. "But when the genetic mutation is present, too, we found a clear cost for what otherwise appears to be a benign effect of extra IGF2."

The team's analysis of colon tissue samples from a dozen or so Johns Hopkins patients with suspected colon cancer suggests that IGF2's effect in people may be similar, the researchers report. A larger study of samples from patients with and without suspected colon cancer is underway, Feinberg notes.

In the mice -- as well as in about 30 percent of colon cancer patients and 10 percent of the general population -- the extra IGF2 stems not from a genetic problem, or mutation, but an "epigenetic" problem that improperly turns on the copy of the IGF2 gene that should remain off.

Unlike most genes, the copy of IGF2 that should be silent depends only on which parent it came from, a situation called genomic imprinting. For IGF2, the copy inherited from the mother is always supposed to be turned off.

In the mice and in some people, however, cells lack the epigenetic "marks" that sit on the DNA and keep the maternally inherited copy turned off. As a result, cells make a double dose of the IGF2 protein and are said to have "loss of imprinting" of IGF2.

Although Feinberg and others have already noted an association between loss of imprinting of IGF2 and colon cancer in people, the current experiments were designed to find out whether the loss of imprinting is involved in cancer's development or just in its progression.

"Most researchers, including me, expect epigenetic differences to influence progression -- whether a tumor would grow slowly or quickly, or whether it would spread," says Feinberg. "But, in this case, our results show that loss of imprinting of IGF2 contributes to colon cancer's development in the mice. It doesn't cause tumors directly, but it creates an environment which is ripe for cancer to start."

Because precursor cells in the colon's lining had been identified as a likely starting point for tumors, Feinberg and his team tossed a cancer-causing genetic mutation into the mix. The IGF2 mice were crossed with mice carrying a mutation in a gene called APC, which had been tied to colon cancer by researchers studying families with excessive growths, or polyps, in the colon.

Mice with extra IGF2 and the APC mutation developed twice the number of tumors as mice with the mutation but whose IGF2 levels were normal. The tumors grew at the same rate in both sets of mice, suggesting that more tumors get started in the mice with extra IGF2, notes Feinberg.

"In the mice, loss of imprinting of IGF2 roughly doubles the risk that the genetic mutation will cause a tumor," says postdoctoral fellow Atsushi Kaneda, Ph.D. "Double the risk may not seem like much, but this loss of imprinting is common."

The researchers' mice mirror two situations in people because the double dose of IGF2 was accomplished in two ways. One set of mice, obtained from Shirley Tilghman at Princeton, have a double dose of IGF2 because they are missing another gene, H19, whose sequence overlaps the region that usually shuts off one copy of IGF2. As a result, these mice lack H19 and have double IGF2.

To isolate the effect of the extra IGF2, Rolf Ohlsson at the Uppsala University, Sweden, developed a set of mice missing only the control region for IGF2; their H19 gene was intact. These mice likely mimic the 30 percent of colon cancer patients and 10 percent or so of the human population who have loss of imprinting of IGF2.

Only the Princeton mice have been crossed with the APC mice. Both the Princeton and the Swedish mice have the extra precursor cells in the lining of the colon, suggesting the effect on cancer development would be similar.

Co-author Dan Longo, M.D., of the National Institute on Aging notes that the mice with both double IGF2 and the APC mutation should be a useful animal model to evaluate the impact of colon cancer prevention strategies, including dietary interventions and targeted drugs.

CK2 protein sustains colon cancer cells by stopping apoptosis

Fri, 25 Feb 2005 18:27:38 PST

( from http://www.rxpgnews.com ) A protein called CK2 plays a deadly role in colorectal carcinoma by blocking the ability of these tumors to activate a natural self-destruct mechanism that would clear this cancer from the body.

The renegade CK2 protein keeps the tumor alive and growing by desensitizing the cancer cells to the effects of another protein called TRAIL. Normally, TRAIL triggers apoptosis (cell suicide) in the cancer cells as a way of protecting the body. CK2 is an enzyme composed of four small proteinstwo alpha proteins and two beta proteins.

The finding holds promise for developing drugs that help a patients cancer cells become sensitized to TRAIL-induced apoptosis. For example, treating the tumors with TRAIL to trigger apoptosis while blocking CK2 might enhance anti-cancer treatment for a variety of other solid tumors, such as pediatric rhabdomyosarcoma, according to Janet Houghton, Ph.D., a member of St. Jude Hematology-Oncology. Rhabdomyosarcoma is a tumor originating in cells that have some features of muscle cells.

The St. Jude team showed that CK2 exerts its anti-apoptosis effect within a structure called DISC (death-inducing signaling complex). The DISC is a large jumble of proteins that interact with each other after TRAIL binds to the outer cell membrane. After DISC forms, an enzyme called caspase-8 triggers the cascade of biochemical events outside DISC that eventually leads to cell death. By desensitizing the cell to TRAIL, CK2 disrupts the DISC response, which in turn prevents apoptosis and allows the cancer cell to continue growing.

The work my laboratory has done using our cell lines of colorectal cancer to investigate the role of CK2 in tumors is now bearing fruit, said Houghton, senior author of the Oncogene report. Weve shown in some detail how CK2 helps cancer cells survive the natural tendency for abnormal cells to self-destruct, as well as how to block CK2 and permit the cell to undergo apoptosis. In doing so, weve begun to map out a strategy for making cancer cells more likely to self-destruct.

The findings of the current study support and expand those published by Houghtons laboratory last October in the journal Clinical Cancer Research. In that study, the team reported similar findings in rhabdomyosarcoma cells.

In the current study using human colon carcinoma cells, the researchers found that while CK2 usually is continually active, they could block this activity using a CK2-inhibitor called DRB.

Subsequently, the team showed that blocking CK2 with DRB made the cells very sensitive to TRAIL, causing them to commit suicide. This proved the important role CK2 played in preventing TRAIL-induced cell suicide. However, DRB did not have an effect on normal cells, which strongly suggests that CK2 blocks apoptosis only in cancer cells.

Because DRB can also interfere with other cellular reactions, the researchers blocked CK2 using another technique: short hairpin RNA (sh RNA). This technique uses a tiny bit of genetic material specifically designed to shut down a particular genein this case, the gene for the alpha proteins that make up part of CK2. Again, CK2 activity was lost, the cancer cells were sensitized to TRAIL, and the cells committed suicide.

The researchers also showed that the ability of TRAIL to trigger apoptosis depended on caspase enzymes, such as caspase-8. Caspase enzymes are part of the biochemical pathway that triggers the cell to undergo apoptosis. Specifically, when the team added to the cancer cells a drug that blocks caspases, TRAIL-induced apoptosis was also blocked.

Our discovery that blocking CK2 makes cancer cells sensitive to TRAIL-induced cell suicide is very promising, said Kamel Izeradjene, Ph.D., a postdoctoral student in Houghtons lab who did much of the work reported in Oncogene. We hope to find effective drugs that block CK2 in samples of tumors removed from children treated at St. Jude.

This is a translational research laboratory, Houghton said. Our aim is to translate discoveries made here into better treatments for children with solid tumors.

Grant Awarded For Study of Tumor-Specific DNA Mutations Involved in Colorectal Cancer

Thu, 24 Feb 2005 06:59:38 PST

( from http://www.rxpgnews.com ) Perlegen Sciences, Inc. announced today that it has been awarded a grant from the National Cancer Institute (NCI) to study tumor-specific DNA mutations involved in colorectal cancer in collaboration with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The research could lead to a better understanding of the disease, improved tools for cancer detection and diagnosis, new targets for therapeutic and preventive intervention, and opportunities for more individualized treatment.

In an effort to identify and characterize cancer genes, the team will analyze at single-base resolution the DNA sequences of thousands of genes in colorectal tumor tissue as well as in normal tissue from the same patients.

This effort is expected to lead to the identification of a significant number of tumor-specific mutations, providing insight into the cause of disease.

The large-scale identification and characterization of genes mutated in cancer will advance our understanding of the mechanisms by which malignant cells arise from their normal progenitors, stated Andrew Sparks, PhD, Director of Association Studies at Perlegen Sciences and Principle Investigator of the study. We are excited to be working on this important issue with the distinguished cancer investigators at Johns Hopkins.

Another molecular player in colon cancer initiation identified

Thu, 03 Feb 2005 00:25:38 PST

( from http://www.rxpgnews.com ) Gastric and colorectal cancers account for more than 1 million deaths worldwide every year and several research groups have been working to identify the molecular events that result in the initiation and progression of these tumors. It has been established that interfering with the function of one gene, called Adenomatous Polyposis Coli (APC) has a profound effect on the cells lining the innermost layer of the colon (called the epithelium) and causes them to lose control over their proliferation leading to tumors.

Now Klaus Kaestner from the University of Pennsylvania School of Medicine has headed a study that identifies another molecular player influencing the initiation of colon cancers.

This study will be published in the February 1 issue of the journal Genes and Development.

An animal model with an inactivating mutation within the mouse equivalent of the APC gene displays very similar pathology as seen in human colon cancers and develop tumor growths called polyps in their colons, eventually leading to death. Inactivating the APC gene was found, as in human cells, to cause the accumulation of a protein called beta-catenin in the nuclei of these cells.

Kaestner's group had earlier published research on a transcription factor called Foxl1 that is also expressed in the colon, but in a different layer of cells, adjacent to the epithelium, called the mesenchyme. They had seen that mice that are deficient for the Foxl1 protein show a similar accumulation of the beta-catenin protein in the epithelium layer, yet they do not get cancers. However, combining the Foxl1 deficiency with an inactive APC gene had drastic outcomes. The group compared animals that were partially deficient for APC (containing one normal copy of the APC gene and one mutant inactive copy) in the presence or absence of Foxl1. Both animals developed tumors, however, in the absence of Foxl1, tumor frequency was more than 7-fold higher.

In addition, the animals developed tumors in the stomach. None of the tumors seen in either case were invasive leading to the conclusion that the Foxl1deficiency affects early stages in tumor formation. Additional analysis revealed that the Foxl1 deficiency affected the onset of tumor formation, accelerating them to arise in 1/3rd of the normal time. The authors examined the integrity of the APC gene in these tumor cells and found that more than ninety per cent of the tumors had lost the normal copy of the APC gene and now were completely deficient.

What is the significance of these results on understanding the initiation of colon cancer? A deficiency of Foxl1 in the mesenchymal layer of the colon leads to altered signaling to the epithelium layer and results in increased cell proliferation and turnover of this layer. In people with a genetic predisposition, like those with Familial Adenomatous Polyposis, or environmental stress that generates a spontaneous mutation in the APC gene, mutations in the Foxl1 gene or its targets may dramatically increase the likelihood that the second normal copy of the APC gene is lost or mutated, leading to the initiation of tumor formation.

This study sets a new paradigm for gastrointestinal tumorigenesis, in that genetic events outside the epithelial layer itself have a profound effect on tumor initiation. Thus it appears likely that this study will foster additional research into other mesenchymal genetic modifiers, and into potential therapeutic approaches that affect the signaling between the two cell layers.

Oxaliplatin-Bevacizumab Combination Regimen Shows a Better Survival Advantage in Advanced Colorectal Cancer,2 studies show

Mon, 31 Jan 2005 20:25:38 PST

( from http://www.rxpgnews.com ) Sanofi-aventis announced today preliminary results of two large prospective trials evaluating the safety and efficacy of Eloxatin(R) (oxaliplatin for injection)-based regimens in the treatment of metastatic colorectal cancer.These data were presented at the Gastrointestinal Cancers Symposium, co-sponsored by the American Society of Clinical Oncology (ASCO), the American Gastroenterological Association (AGA), the American Society for Therapeutic Radiology and Oncology (ASTRO), and the Society of Surgical Oncology (SSO).

TREE-2 is the first study to assess the safety of oxaliplatin-based regimens combined with bevacizumab for the first-line treatment of metastatic colorectal cancer. Preliminary efficacy results suggested that adding bevacizumab improved the response rate of all oxaliplatin-based regimens.

Researchers from the Eastern Cooperative Oncology Group (ECOG) also reported results of the E3200 study, which demonstrated a significant 26 percent reduction in the risk of death for patients receiving oxaliplatin-based chemotherapy (FOLFOX4) plus bevacizumab compared to those who received oxaliplatin alone. Although patients in the E3200 study had previously been treated for advanced or metastatic colorectal cancer, median overall survival with oxaliplatin-based chemotherapy plus bevacizumab was 12.5 months compared to 10.7 months with oxaliplatin alone.The difference is statistically significant and corresponds to a 17 percent improvement in median overall survival in this
previously treated patient population.

The randomized, multicenter TREE-2 (A Randomized, Prospective Study Comparing Three Regimens of oxaliplatin Plus Fluoropyrimidine and Bevacizumab for Evaluation of Safety and Tolerability in First-Line Treatment of Patients with Advanced Colorectal Cancer) is the first study evaluating the safety and tolerability of bolus, infusional, and oral fluoropyrimidine + oxaliplatin-based regimens combined with bevacizumab for the first-line treatment of metastatic colorectal cancer.

In the TREE-2 study, 213 adults aged 18 or older with metastatic colorectal cancer were treated with one of three oxaliplatin-containing chemotherapy regimens: oxaliplatin plus infusional 5-fluorouracil/leucovorin,oxaliplatin plus bolus 5FU, and oxaliplatin plus capecitabine,all used in combination with bevacizumab.The preliminary results of TREE-2 assessed the tolerability of the three oxaliplatin/fluoropyrimidine regimens with bevacizumab. There were no unexpected toxicities.The best treatment response rates were seen when bevacizumab was added to oxaliplatin or capecitabine. Full efficacy results are expected to be presented at the 2005 ASCO Annual Meeting in May 2005.

The E3200 study, a phase III randomized study of oxaliplatin, fluorouracil, and leucovorin calcium with or without bevacizumab versus bevacizumab alone in patients with previously treated advanced or metastatic colorectal
adenocarcinoma , was sponsored by the National Cancer Institute (NCI) and conducted by a network of researchers led by the ECOG.A total of 829 patients were enrolled in the study between October 2001 and April 2003.

Preliminary results were announced in December 2004. Sanofi-aventis provided oxaliplatin for the trial under its Cooperative Research and Development Agreement (CRADA) with the NCI for the clinical development of oxaliplatin.

Oxaliplatin, used in combination with infusional 5-FU/LV, is indicated for adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor. The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow-up of 4 years.

Oxaliplatin, used in combination with infusional 5-FU/LV, is indicated for the treatment of advanced carcinoma of the colon or rectum.

Oxaliplatin should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylactic-like reactions to oxaliplatin have been reported and may occur within minutes of oxaliplatin administration. Epinephrine, corticosteroids, and
antihistamines have been employed to alleviate symptoms, and discontinuation of oxaliplatin therapy may be required.

In Adjuvant Colon Cancer Setting,the incidence of grade3 or grade4 events was 70% and 31% on oxaliplatin combination arm and infusional 5-FU/LV arm, respectively. Granulocytopenia,paresthesia, diarrhea, vomiting,and nausea were the most common grade3 or 4 adverse events.Paresthesia was seen in 92% of patients on the oxaliplatin combination; 21% had residual paresthesia at 18-month follow-up.Three percent and 0.5% had grade2 and 3paresthesias,respectively, at 18-month follow-up.Grade 3 or 4 hypersensitivity was noted in 3% and may require discontinuation of therapy. Hepatotoxicity, evidenced by increase in transaminases(57% vs 34%) and alkaline phosphatases (42% vs 20%),was observed more commonly in the oxaliplatin arm.The incidence of increased bilirubin was similar on both arms.Hepatic vascular disorders should be considered and investigated if abnormal liver function tests or portal hypertension are present and cannot be explained by liver metastases or other known etiologies.
~~~~~~~~
Sanofi-aventis is the world's 3rd largest pharmaceutical company, ranking number 1 in Europe. Backed by a world-class R&D organization, sanofi-aventis is developing leading positions in seven major therapeutic areas:
cardiovascular disease, thrombosis, oncology, diabetes, central nervous system, internal medicine, vaccines. Sanofi-aventis is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).

New option for non-invasive colorectal cancer testing

Thu, 23 Dec 2004 22:00:38 PST

( from http://www.rxpgnews.com ) A new option for non-invasive colorectal cancer testing may encourage some people who avoid screening for the deadly disease to be tested.

A study published in the December 23 issue of the New England Journal of Medicine reports that a non-invasive test for DNA mutations present in stool has an encouraging rate of detecting colorectal cancer compared to the standard non-invasive method -- fecal occult (hidden) blood stool testing, although neither approached the detection rate of colonoscopy, an invasive procedure.

"A simple, non-invasive test that detects tumor-specific products with reasonable sensitivity and specificity might overcome barriers to screening among persons who are not willing to have a more invasive test, such as colonoscopy," said Thomas Imperiale, M.D., professor of medicine at the Indiana University School of Medicine and a research scientist at the Regenstrief Institute.

The study, conducted at 81 sites by Dr. Imperiale and colleagues of the Colorectal Cancer Study Group, reports that in average risk, asymptomatic individuals the fecal occult blood test -- which tests blood hidden in stool -- found only 13 percent of colorectal cancer; while the new stool DNA test detected 52 percent of the cancers. Colonoscopy, which is presumed to find all colon cancers, is the "gold standard" against which all other tests are measured.

Typically, colorectal cancer develops slowly over a period of several years, usually beginning as a growth of tissue known as a polyp that develops on the lining of the colon or rectum. Most cancerous lesions bleed intermittently, however many precancerous polyps do not bleed. Absence of fecal occult blood cannot rule out cancer or precancerous lesions.

Previous studies have found that polyps as well as cancerous lesions may shed abnormal DNA. It is this DNA which the stool DNA panel analyzes. Although researchers found that the majority of precancerous polyps discovered during colonoscopy were not detected by either non-invasive test, they report that the stool DNA panel detected a greater proportion than did analysis of stool blood.

Despite national guidelines recommending screening, fewer than half of American adults aged 50 years and older have had a recent examination for colorectal cancer at the proper interval according to Centers for Disease Control.

"There are many reasons why people don't get screened for colon cancer," said Dr. Imperiale. "Some individuals do not want colonoscopy because of discomfort despite conscious sedation, its inconvenience, or its risk for complications; others are unwilling to smear stool samples on a card for the occult blood test every year." The stool DNA panel test, which requires a single sample expelled from the body directly into a container, gives people who are not getting screened with any of the currently available methods, another noninvasive option.

According to the American Cancer Society colon cancer is the third leading cause of cancer death among men and women in the United States.

Researchers discover new gene in colon cancer

Mon, 13 Dec 2004 18:33:38 PST

( from http://www.rxpgnews.com ) Cancer researchers at the Case Western Reserve University (Case) School of Medicine, University Hospitals of Cleveland (UHC) and the Howard Hughes Medical Institute have found a "Celebrex-like" gene that suppresses the growth of colon cancer. The researchers discovered that the gene, called 15-PGDH, is found in normal cells and is virtually undetectable in colon cancer cells. When the researchers restored the gene in tumor cells and injected them into immune-deficient mice, the mice showed little or no tumor development. The study appears in the Dec. 14 issue of the Proceedings of the National Academy of Sciences.

The gene 15-PGDH acts as an antagonist to control an enzyme called COX-2. An increase in COX-2 is a major early event in the genesis of human colon tumors.

Sanford Markowitz, M.D., the Francis Wragg Ingalls Professor of Cancer Genetics at Case and UHC and senior author of the paper, said, "This gene may represent the first of a one-two punch in colon cancer. In colon cancers a dramatic increase of COX-2 is seen. 15-PGDH would act to antagonize and check this increased COX-2 activity. Without 15-PGDH present,unchecked COX-2 goes on to cause abnormal changes on the cellular level, which may lead to tumor development."

Previous studies have shown that patients who take nonsteroidal anti-inflammatory drugs (NSAIDs), which are COX-2 inhibitors, have a lower incidence of colon cancer. COX-2 inhibitors have been shown to shrink the size of tumors in mice. Markowitz likens the 15-PGDH gene to a naturally occurring COX-2 inhibitor. (Celebrex, a popular arthritis drug, is also a COX-2 inhibitor.)

Markowitz found that 15-PGDH is directly controlled and activated by another gene, called TGF-beta. Normally, TGF-beta sends a signal that allows the colon to shed cells weekly as a way of helping to block development of colon cancers. In 1995, Markowitz discovered colon cancers have mutations that inactivate the TGF-beta pathway.

"If there is no TGF-beta signal, there is no 15-PGDH. That means the opponent to COX-2 is gone, and the COX-2 oncogene activity is unopposed," said Markowitz. "This interaction between TGF-beta and 15-PGDH points to the importance of the TGF-beta system in suppressing colon cancer. These genes give us targets that we can aim for in the development of new drugs or gene therapies that may help us treat or prevent colon cancer," said Markowitz, who is also an investigator with the Howard Hughes Medical Institute.

Lead authors on the paper are Min Yan of the departments of medicine, molecular and microbiology at Case Western Reserve University School of Medicine and the Ireland Cancer Center at University Hospitals of Cleveland, and Ronald M. Rerko of Howard Hughes Medical Institute. Also involved were researchers from the University of Kentucky and the Protein Design Laboratories in Freemont, Calif.