Studying the ABCs of UGTs

Every year, more than 50,000 people in the United States die of colorectal cancer. Studies have shown that regular use of ordinary aspirin reduces colon cancer risk by 50 percent in some people, but it has no effect in others. Now, researchers in the Public Health Sciences Division are in the final stages of recruiting volunteers for a study to better understand how certain genes may affect aspirin's protective effect.

Differences in metabolizing enzymes may explain why some, but not all, people benefit from aspirin. The enzymes are proteins that help process and break down medicines, including aspirin. Dr. John Potter, principal investigator of the Aspirin and the Biology of the Colon Study (ABC), is studying specific metabolic enzymes called glucuronosyltransferases (UGTs). UGTs exist in several forms in the body, and their activity varies between individuals due to genetic differences.

"These enzymes process aspirin so that it is excreted in the urine," said Project Coordinator Lisa Levy. "Some people get rid of aspirin very quickly, while others may get rid of it more slowly. These may be the differences that guide aspirin's effectiveness."

Previous studies have shown that individuals who use aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) are at lower risk for colon cancer or polyps, small growths in the colon that can develop into cancer. Earlier work by Dr. Johanna Lampe, one of the co-investigators, and colleagues showed that individuals who used aspirin or NSAIDs and had a particular genetic variation in the UGT enzymes had a lower risk for colon polyps than those with the more common genetic profile. This particular genetic pattern is found in only 10 percent of the population, and it raised the question of whether these individuals respond differently to aspirin.

The NCI-funded, two-part study is recruiting about 380 men and women, ages 21 to 45, from the greater-Seattle area. Recruitment began about three years ago. Most study visits take place in the Prevention Center in the Robert M. Arnold Building.

In the first part of the study, participants — who cannot smoke or take any prescription medications, nor be pregnant or breastfeeding, among other criteria — complete health surveys, take two aspirins, collect eight hours' of urine and have blood drawn the next day.

UGT genetic profiles

Each participant's blood sample is analyzed to determine the UGT genetic pattern, and the urine sample shows how quickly the person breaks down aspirin. The data from the 380 study members will be used to describe what genetic and lifestyle factors (like diet) affect aspirin metabolism. About 30 percent of the participants cannot participate in the second part of the study because they have a mixed-type UGT genetic pattern.

"Our goal is to get 380 blood samples in order to find the 40 participants that match our criteria," Levy said, indicating that she needed to enroll about 60 more participants to meet the recruitment aim. "Because this study is so targeted, it's like a giant funnel. We start out with a large number of which only a small subset are eligible."

Study members who qualify are asked to join the second part of the study. During this 8-month segment, the researchers are looking at the effects of aspirin on the colon in a double-blinded clinical trial. Participants take one study pill (aspirin or placebo) daily for two months. After that period, they have a sigmoidoscopy (an examination of the colon with a flexible scope) performed and have colon biopsies taken at the Seattle Cancer Care Alliance clinic. About three months later, the pill taking and tests are repeated. The biopsies are analyzed for changes in colon-cell biology using microarrays which allow for the measurement of thousands of genes at once.

"This crossover intervention where we test both the aspirin and the placebo in the same person will give us the strongest and most efficient test of the genetic component," Lampe said. "And because the study participants are selected on the basis of their UGT genetic profiles, we can be sure to recruit a sufficient number of the rarer profiles."

"Ultimately, the results from studies like these may help us tailor our cancer prevention recommendations," Lampe said. "We may offer cancer prevention advice that takes a person's genetic profile into consideration, but we still have a lot of questions to answer first."

Those interested in participating can learn more on the ABC study's Web site.