Scientists at Jefferson Medical College believe they’ve uncovered a molecular mechanism by which aspirin(Drug information on aspirin) interferes with colorectal cancer development in individuals who carry particular gene mutations that make them very likely to get the disease.
“Aspirin is a well-known prophylaxis for cancer,” said molecular geneticist Richard Fishel, phd, professor of microbiology and immunology at the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia, who with Josef Ruschoff, md, of the University of Regensburg, Germany, led the research. “The new twist is that aspirin suppresses the accumulation of mutations that are the cause of a common inherited cancer.” Similar mutations are found in 5% to 10% of sporadic colorectal, endometrial, and ovarian cancers. Their work appeared September 15th in the Proceedings of the National Academy of Sciences.
Drs. Fishel, Ruschoff, and their colleagues examined human colon cancer cell lines with defective mismatch repair genes, which are necessary to fix normal cell damage that occurs when cells divide and multiply. These mismatch repair genes were discovered by Dr. Fishel and Dr. Richard Kolodner (now at the Ludwig Institute for Cancer Research in San Diego) in 1993 to be the cause of hereditary nonpolyposis colorectal cancer (HNPCC), the most common form of hereditary cancer.
The scientists then treated the colon tumor cells with two nonsteroidal anti-inflammatory drugs known to prevent cancer: aspirin and sulindac(Drug information on sulindac). They found that the drugs largely suppressed the genetic instability that underlies the development of cancer in HNPCC. “Our results appear to suggest a very simple treatment for a common hereditary cancer predisposition syndrome,” Dr. Fishel said.
Nonsteroidal anti-inflammatory drugs, such as aspirin and sulindac, are generally thought to work through the prostaglandin pathway via cyclooxygenase (COX). The study by Drs. Ruschoff and Fishel suggests that COX is not involved.
Aspirin as a Tumor Suppressor
For a normal cell to become a tumor cell, many mutations must occur. The accumulation of multiple mutations implies genetic instability. Aspirin suppresses that accumulation of these mutations.
“Even sporadic [non-hereditary] cancer may be considered to be a genetic disease because a large number of mutations must accumulate in the tumor cells,” said Dr. Fishel. “Aspirin screens for cells that are genetically stable, providing a true genetic selection against such forms of cancer. The important point here is that this [aspirin] is an inexpensive over-the-counter drug that anyone can take. When we first discovered the connection of mismatch repair genes to hereditary cancer, there was really nothing we could recommend to families besides increased [and sometimes painful] surveillance. Now we may actually be able to prevent the disease in these individuals and allow them to lead normal lives.”
According to Dr. Fishel, other researchers have shown that taking aspirin reduces the incidence of sporadic colorectal cancer in the population. “That tells you that in some fraction of the population, aspirin has some efficacy. Our results would suggest that the tumors which are most affected by aspirin may arise from having damaged mismatch repair genes. In other words, you are really only suppressing the class of tumors that are caused by having these altered genes.”
Mismatch Repair Genes
When mismatch repair genes go awry, commonly the result is colon cancer. Such genes are part of the intricate molecular machinery that fixes the cellular DNA when for some reason, cell replication doesn’t work correctly. According to Dr. Fishel, MSH2 and MLH1 are the most frequently altered genes in HNPCC, which accounts for some 10% to 15% of all colorectal cancers.
A mismatch of the DNA nucleotides, or building blocks, may occur during cell replication. In replication, precise nucleotide pairing is essential. In human cells, a protein complex containing hMSH2 attaches to mismatched nucleotides. The cellular repair machinery, with hMLH1, then orchestrates the correction of these errors.
“Without hMSH2 or hMLH1 the cellular DNA becomes unstable, errors accumulate, and the result is cancer,” Dr. Fishel explained. “Now the question is, will it work in humans? We already know there is some efficacy in humans. We didn’t know why—this work at least partially answers that question,” said Dr. Fishel.
Future Studies
“This is an important step for cancer prevention in HNPCC,” said Dr. Henry Lynch of Creighton University and one of the discoverers of HNPCC (also called Lynch’s syndrome). “Drs. Fishel and Ruschoff’s work provides a basic research foundation to helping individuals with this devastating disease.”
One next step already underway is a clinical trial in Europe to study the effectiveness of higher doses of aspirin in preventing hereditary colorectal cancer. Dr. Lynch, Dr. Fishel, and Dr. John Burn (University of Newcastle, England and leader of the European Study) are currently organizing the international hereditary colorectal cancer prevention trial using aspirin.
There is a down side to aspirin and sulindac: These drugs have already been shown to harbor some gastrointestinal toxicity and liver toxicity, respectively. “In the future, we would like to understand the specific mechanism and the exact target for the genetic suppression as well as minimize the toxicity,” Dr. Fishel said. “Not everyone can take aspirin. This has to be done the right way and in consultation with a physician.”
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