Research findings presented today at the International Symposium on Antimutagenesis and Anticarcinogenesis at New York Medical College suggest the pain reliever acetaminophen may prevent early biological changes that can lead to colon cancer in laboratory rats.
"In what is considered to be a building body of evidence, we observed that even low levels of acetaminophen showed a powerful protective effect in colon cells exposed to the carcinogen," said lead researcher Gary M. Williams, M.D., professor of pathology at the College, who noted these findings support those of his earlier research on acetaminophen. Acetaminophen is the active ingredient in Tylenol and other pain relievers.
"The fact that we found this protective effect even in animals exposed to much higher doses of the carcinogen than a human would ever encounter suggests that acetaminophen may have the potential to help prevent the onset of this disease in humans," Dr. Williams said.
According to Dr. Williams and his colleagues, these findings applied to animals only, and more animal research is needed before humans can be studied in clinical trials. Therefore, they cautioned that as with any medication, people should read the acetaminophen label carefully and use the product only as directed.
In the controlled study by Dr. Williams, test animals were divided into treated animals and controls. Treated animals received acetaminophen prior to their exposure to varying doses of 3,2’-dimethyl-4-aminobiphenyl, a chemical agent linked to colon cancer. Control animals were exposed to the same doses of the carcinogen, or cancer-causing chemical, but were not pretreated at all.
Dr. Williams explained that in animals that were not pretreated with acetaminophen, cellular changes recognized as common precursors to colon cancer were present. In contrast, the animals that were treated with acetaminophen prior to exposure were significantly protected against the cellular effect of the chemical agent.
"In fact, we found that cellular changes indicative of colon cancer were either eliminated or reduced by half in animals pretreated with acetaminophen," said Dr. Williams.
The research presented at the symposium was sponsored in part by an unrestricted grant from McNeil Consumer & Specialty Pharmaceuticals, makers of Tylenol®.
April 2, 2002 - Gene Alteration Spurs Growth of Colon Cancer
Researchers have discovered a novel gene alteration that causes an abnormal cellular "off-switch" that contributes to the growth of colon cancer. Identification of the gene alteration, which appears to contribute to tumor malignancy in about 40 percent of patients with colon cancer, may permit researchers to better understand how tumors become malignant and invasive.
Howard Hughes Medical Institute investigator Sanford D. Markowitz and colleagues at Case Western Reserve University and four other institutions have shown that inactivation of the helicase-like transcription factor (HLTF) gene contributes to transforming normal colon cells into cancer cells. The gene is a member of a family of genes that removes the proteins that coil around DNA, thus exposing individual genes to the cell’s gene-expression machinery. HLTF proteins help stabilize DNA and regulate the production of other proteins in the cell.
"HLTF belongs to a pathway that is just beginning to be appreciated in the development of cancer," said Markowitz. "This is the first time a protein in this family has been implicated as a participant in a major, common form of cancer." Markowitz and his colleagues reported their findings in the April 2, 2002, edition of the Proceedings of the National Academy of Sciences.
"This is a new colon cancer suppressor gene whose inactivation appears to contribute to malignancy in about 40 percent of cases," said Markowitz. "Understanding what this gene does in the cell will help us comprehend how colon cancer gets started and could be a new target for drug intervention."
In the study, the scientists examined colon cancer cells and normal cells from 63 colon cancer patients and 34 colon cancer cell lines grown in the laboratory. They discovered that production of the HLTF protein had been shut down by a mechanism called DNA methylation.
"This type of methylation produces an abnormal ‘off switch’ that in this case inappropriately shuts down production of a tumor suppressor protein," said Markowitz. The methylation process has also been implicated in turning off other tumor suppressor genes and is recognized as a contributor to the development of cancer.
When the scientists introduced a functional copy of the HLTF gene into the colon cancer cell lines that lacked the gene, the cells stopped growing. This finding suggests that the HLTF gene is itself a tumor suppressor gene that can stop tumors from growing.
Markowitz said that the studies also hint that drugs that reverse methylation may be a new type of cancer treatment. These drugs are now in the early stages of development. In the short term, however, Markowitz believes the finding may help doctors diagnose colon cancer and perhaps differentiate aggressive, invasive tumors from less aggressive forms of colon cancer.
When Markowitz and his colleagues looked in lung and breast cancer cells, they found the HLTF gene was normal. Based on this result, they concluded that the HLTF gene may be involved specifically in colon cancer progression. Furthermore, the scientists had previously detected abnormal methylated DNA in the blood of some colon cancer patients, suggesting that if the findings hold for the commonly methylated HLTF gene, it could be a target for a new diagnostic test for colon cancer. Markowitz cautioned that the result needs to be duplicated and other cancer cells need to be tested.
Markowitz is optimistic, and he cites recent work by HHMI investigator Bert Vogelstein at The Johns Hopkins University School of Medicine that demonstrates a new targeted, non-invasive test for finding about half of colon cancers using the APC tumor suppressor gene.
"What has limited the development of a simple diagnostic test for colon cancer previously has been finding the right target that can catch close to all the cases," said Markowitz. "What we describe in this paper is a test that can catch 40 percent of colon cancers. A screen that searches for APC and HLTF mutations may be able to catch more than 90 percent of cancers, making blood or stool sampling practical."
The development of a simple, non-invasive colon cancer diagnostic test could greatly increase early detection of the second leading cause of cancer death among adult Americans, said Markowitz. A blood or stool test is seen as a way of significantly increasing the number of people whose colon cancer is detected in the early stages of growth when the prognosis for full recovery is good. By contrast, colonoscopy, the current standard for detection, is invasive, so people tend to put off or avoid having the test.
The scientists also found that those tumors with the silenced HLTF gene were actually less likely to spread to adjacent tissues. The results suggest that tumors with HLTF turned off may grow more slowly than other tumors.
"In the patient group we studied, the patients with abnormal HLTF seemed to do somewhat better," he said. "This suggests testing for HLTF mutations may have some prognostic value in determining how aggressive the cancers are."
Markowitz added that the combination of applying modern molecular techniques and identifying key targets such as HTLF should make colon cancer diagnosis and treatment easier, as well as providing more information about the severity of the disease.
March 14, 2002 - Dietary changes can lower colon cancer risk in families with a history of the disease; folic acid and multivitamin can help
People who have a parent or sibling with colon cancer can markedly reduce their own chances of developing the disease by taking a daily multivitamin that includes folic acid and limiting their intake of alcohol, according to a new study by researchers at Dana-Farber Cancer Institute, Brigham and Women’s Hospital and Harvard School of Public Health.
The findings, published in the March issue of Cancer Epidemiology, Biomarkers and Prevention, join a small but growing body of evidence that dietary and behavioral changes can reduce the risk of some cancers in people who may have an inherited tendency to develop them.
"Previous research has demonstrated that people’s risk of developing colon cancer is two times greater if they have a parent or sibling who has been diagnosed with the disease," says study leader Charles Fuchs, MD, of Dana-Farber. "Our study points to steps that such individuals can take to substantially lower those odds."
With approximately 135,000 new cases reported each year, colon cancer is the third most commonly diagnosed cancer in the United States, and it is one of the leading causes of cancer-related deaths. Studies have shown that a variety of diet and behavioral modifications -- such as stopping smoking, eating a diet high in fruits and vegetables, avoiding heavy red meat consumption, and having regular colon exams after age 50 -- can reduce colon cancer risk in the general population. In the new study, Fuchs and his colleagues asked whether any of these measures are especially effective in people with a family history of the disease.
For answers, the researchers turned to the Nurses’ Health Study, a project which has been tracking the health of 121,700 female registered nurses in the United States for more than 25 years. The study, run by researchers at BWH, maintains an extensive databank of participants’ dietary and lifestyle habits, making it possible to explore the relation between people’s behavior and their risk of developing certain diseases.
Fuchs, who is also on staff at BWH and an assistant professor of medicine at Harvard Medical School, analyzed information from 88,758 nurses whose family health histories and dietary habits were recorded in the database. He focused on behaviors known to be associated with colon cancer to see if any were particularly helpful or harmful in people with a family history of the disease.
He found three: A diet high in folic acid, high in methionine (an essential amino acid), and low in alcohol intake, when followed at least five years, reduced colon cancer risk much more sharply in those with first-degree relatives who had the disease than in those without such a family history. Although all the study participants were women, Fuchs contends there’s no reason to think the results do not apply to men as well.
Participants with a family history of colorectal cancer who consumed low-folate diets were 2.5 times more likely to develop colon cancer than similar individuals who did not have a family history. In contrast, among participants on a high-folate diet, those with a family pattern of colorectal cancer did not experience any significant increase in colon cancer risk compared to those without such a pattern. "It appeared that either a high-folate diet or use of folate-containing multivitamins virtually eliminated the excess risk of colon cancer associated with a family history of the disease," Fuchs explains.
While folic acid is found in fruits and vegetables and products made with enriched flour, obtaining the high levels tracked in the study -- 400 micrograms a day -- can be easily achieved by taking a multivitamin, Fuchs says. The quantity of alcohol consumption that appeared to increase the risk associated with a family history was greater than two glasses of wine per day.
The findings around methionine are more complicated. While high levels of the nutrient were shown to reduce the influence of a family history of colorectal cancer on the development of the disease, high amounts also may be associated with the "hardening of the arteries" that can lead to heart attacks. As a result, dieticians do not recommend taking methionine supplements.
The new study not only provides guidance to people with family risks of colon cancer, Fuchs comments, but also may point toward a better understanding of the biology of the disease. Scientists know that folic acid, methionine, and alcohol all affect a process known as "methylation," in which specialized compounds of hydrogen and carbon are attached to various structures and products of cells.
Methylation plays a vital role, for example, in creating the building blocks of DNA within cells. Without sufficient methylation, the DNA structure may become unstable, raising the prospect of certain diseases, including cancer.
It’s possible, Fuchs says, that families with a pattern of colon cancer may have some modest alteration in either DNA processing or repair that makes them particularly susceptible to deficiencies in the methylation process.
"This research may make it possible to identify genes that confer a greater risk of the disease in families with a history of it," Fuchs remarks. "That would be an important step toward therapies able to reduce that risk. Our findings involving folate may offer a first clue."