Can you name the three commonest cancers in the U.S. population?

Here's how epidemiologist Maria Elena Martinez, at the University of Arizona in Tucson, parses that question: "In terms of U.S. incidence, the third most frequent malignancy is colorectal cancer (CRC). In 2003, the rates of men and women combined for the malignancy amounted to 107,500.

"Six percent does not appear to be a huge proportion," Martinez remarked, "but it is the third commonest cancer in the U.S., which makes it an important public health disease. The first two," she continued, "are lung cancer, breast cancer in women and prostate cancer in men. CRC occurs in both sexes."

Martinez is principal author of a paper in the current Proceedings of the National Academy of Sciences (PNAS) titled "Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxyase gene [ODG]." It's pre-dated June 24, 2003.

"There are perhaps more than one message in our finding," Martinez told BioWorld Today. "The first one is that the polymorphism in this CRC gene, called the ornithine decarboxylase gene, is associated in our study with the lower probability of recurrence in the population of colorectal adenomatous recurrence. This is a novel finding," she continued, "because it has never been published in the literature, either in terms of colorectal cancer or colorectal adenomatous polyps.

"Our other novel finding," Martinez went on, "has to do with the exploration of potential mechanisms for why aspirin decreases cancer risk. We think from our experimental work that this is due to a reduction in polyamines, which are products involved in protein biosynthesis and replication. High levels of these are associated with certain levels of cancers. So by deducing them we think they're a likely mechanism that explains the effects of aspirin and of ODC - the ornithine decarboxylase gene. We show that individuals homozygous for the minor ODC A-allele who reported using aspirin are approximately 0.10 times as likely to have an adenoma recurrence as non-aspirin users homozygous for the major G-allele."

Exploring Aspirin Is Main Significance

"The significance of this finding," she continued, "is that now we can explore the mechanism of aspirin. There are various people out there trying to figure out how aspirin reduces cancer risk. So that's one significance. The second one is that those lucky individuals who have this form of the gene as the so-called aa allele. It is present in about 6 percent of the population. These are the people who benefit most from aspirin, who say aspirin is good to prevent development of colorectal cancer. But for those individuals who make up 6 percent of the population, the danger is really diminished - 90 percent of recurrence in the population. You can combine the effects of aspirin and the presence of this dual allele. That is a phenomenal finding.

"So working independently to reduce the risk of polyamines," Martinez said, "what we're proposing is that aspirin increases the metabolism of polyamines - their breakdown - whereas the ODC of the allele increases the synthesis of the polyamines. So when you combine these two together you have a double bang that results in a smart reduction of colorectal cancer. It's an aspirin hypothesis that's true."

Adenomas are nonmalignant precursors of CRC. They carry one, two or thousands of polyps - bulbous growths perched on top of slender upstanding stems. It is thought that most colon cancers arise from adenomatous polyps.

In the year 2000, Martinez and her co-authors conducted and published a large-scale human trial of adenomas and aspirin. "The trial was not a test of aspirin," she recounted. "Rather, it was a negative survey that found no effect of dietary fiber and reduction of adenoma recurrence. We conducted studies such as this one to explore other risk factors in mechanisms involved in aspirin. We consider this study not a trial but an observational survey.

"We assessed people who shop-prescribed their aspirin, not what they manipulated, but who self-prescribed the drug. These were individuals who went to their doctor and were found to have more than one adenomatous polyp in their colon. So on to colonoscopy - full-length endoscopic examination of the colon - and all their polyps were removed. They were then invited to participate in the survey. We followed them two times for a period of approximately three years. During that interval we assessed whether they had a recurrence of their old polyps, new polyps or adenomatous polyps in their colon. We looked at the rate of recurrence among people who said they took aspirin vs. a rate of recurrence in people who didn't. What we found was among individuals who said they took aspirin their rate of recurrence was approximately 30 percent lower than those who didn't. That's one of the results.

"For potential human application," Martinez added, "we say that people who take aspirin for whatever reason, the risk of developing colorectal cancer is lower. But by no means do we say that everyone in the population should go out and take aspirin, because although it does reduce cardiovascular disease, colorectal cancer among others, and stroke perhaps, it does carry some adverse side effects, so safety has to be considered. The main side effects are ulcers - gastrointestinal bleeding. That's the main one for long-term use of aspirin. Even though they're current in a small amount of the population, we caution that aspirin is not entirely safe."

Fine-tuning Polyamine Mechanism

"Gerner, the senior author on this PNAS paper," Martinez said, "is conducting additional experiments to fine-tune the mechanism. He is going to be working looking at levels of polyamines in the actual colon tissue. He will correlate those to the genes to see whether people who have this form of the gene really have lower levels of polyamines at the tissue level."

"These findings," the PNAS paper concluded, "confirm the hypothesis that the ODC polymorphism is a genetic marker for colon cancer risk. They support the use of ODC inhibitors and aspirin, or other nonsteroidal anti-inflammatory drugs (NSAIDS) in combination as a strategy for colon cancer prevention. However, mechanisms responsible for the preventive effects of NSAIDS on colorectal neoplasia remain unresolved."