Aspirin and colon cancer (fwd)

T. Benjamin Csoka (
Tue, 15 Sep 1998 11:09:23 -0700

> Aspirin Decreases Genetic Mutations Associated with Inherited Colon Cancer
> A new study suggests that aspirin will be a useful chemopreventative for Hereditary Colon Cancer patients
> Aspirin may prevent the development of a particular type of common hereditary colorectal cancer in those at high risk for
> the disease.
> Scientists at Jefferson Medical College believe theyíve uncovered a molecular mechanism by which aspirin interferes
> with colorectal cancer development in those individuals who carry particular gene mutations that makes them very likely
> to get the disease.
> "Aspirin is a well known prophylaxis for cancer," says molecular geneticist Richard Fishel, Ph.D., professor of
> microbiology and immunology at the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia, who with
> Josef Rüschoff, M.D., 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 5-10% of sporadic colorectal, endometrial and ovarian cancers.
> Their work appears September 15 in the Proceedings of the National Academy of Sciences.
> Drs. Fishel, Rüschoff 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 the most common form of hereditary cancer known as Hereditary Nonpolyposis
> Colorectal Cancer (HNPCC).
> The scientists then treated the colon tumor cells with two drugs: aspirin and sulindac, which are both nonsteroidal
> anti-inflammatory drugs and known cancer preventatives. 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 says.
> 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," says 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 a normal life."
> 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."
> Non-Steroid anti-inflammatory drugs such as aspirin and sulindac are generally thought to work through the
> prostaglandin pathway via cyclooxygenase (COX). The study by Drs. Rüschoff and Fishel suggests that COX is not
> involved.
> Scientists would like to find substances that reduce the effects of environmental toxicities. Aspirin looks like it will be
> one of them. At least for the mutations that occur as a result of specific genetic defects associated with hereditary and
> some sporadic tumor cells.
> When mismatch repair genes go awry, the result is commonly colon cancer. Such genes are part of the intricate molecular
> machinery that fixes the cellular DNA when for some reason, cell replication doesnít work correctly. According to Dr.
> Fishel, MSH2 and MLH1 are the most frequently altered genes in HNPCC, which accounts for some 10 to 15 percent 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, it is a protein complex containing hMSH2 that 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
> explains.
> "Now the question is, will it work in humans?" says Dr. Fishel. "We already know there is some efficacy in humans.
> We didnít know why--this work at least partially answers that question."
> "This is an important step for cancer prevention in HNPCC", says Dr. Henry Lynch of Creighton University and one of
> the founders of HNPCC (also called Lynch's Syndrome). "Drs. Fishel and Rüschoff'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 downside to aspirin and sulindac: they 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 says. "Not everyone can take aspirin. This has to be
> done the right way and in consultation with a physician."
> According to the American Cancer Society, colon and rectal cancer is the third most common cancer in the nation, with
> some 200,000 new cases diagnosed annually. Approximately 30,000 people die each year from colon and rectal cancer.
> Between 15-30% of colorectal cancers appear to have a hereditary origin and approximately 50% of those involve
> germline mutation of the human mismatch repair genes.