Scientists at Jefferson Medical College believe
theyve uncovered a molecular mechanism by which 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
The scientists then treated the colon tumor cells with two
nonsteroidal anti-inflammatory drugs known to prevent cancer: aspirin
and 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.
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
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
doesnt 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 didnt know
whythis work at least partially answers that question,
said Dr. Fishel.
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 Lynchs syndrome). Drs.
Fishel and Ruschoffs 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.