Findings about anti-cancer agent could make it more effective

04/14/05

WINSTON-SALEM, N.C. – New research has revealed the power behind an anti-tumor agent being studied in the laboratory. The findings, by scientists at Wake Forest University School of Medicine and the National Cancer Institute, could lead to more effective treatment strategies for cancer.

"Our new understanding of how this agent works could help us combine treatments to reach multiple targets," said William Gmeiner, Ph.D., professor of cancer biology at Wake Forest's School of Medicine, which is part of Wake Forest University Baptist Medical Center.

Gmeiner is working under a grant from the National Cancer Institute (NCI) to investigate the agent's potential for treating human cancer. His most recent findings reveal how the compound – called FdUMP[10] – works to damage DNA, the genetic "code" found in all cells.

The results were reported in Anaheim, Calif., today at the American Association for Cancer Research's 96th Annual Meeting and will be published June 1 in Cancer Research.

Eleven years ago, Gmeiner set out to develop a compound that would be more effective and have fewer side effects than fluorouracil, one of the most common chemotherapy drugs for prostate cancer. Laboratory studies show that FdUMP[10] is 300 to 400 times more effective than fluorouracil at killing cancer cells and less damaging to normal cells. In addition to potential for treating prostate cancer, the compound has also proven effective for leukemia and colon cancer cells.

"Now, we have more information about how it's actually killing cancer cells," said Gmeiner. "We knew that it damaged DNA but did not know the mechanism. Our latest research helped us learn what target we're hitting."

Gmeiner designed the agent to inhibit an enzyme (thymidylate synthase) that plays a major role in the rapid growth and division of cancer cells. But his recent research shows that the agent also acts on another enzyme (topoisomerase) that helps cancer cells replicate.

"Inhibiting topoisomerase causes DNA strands to break, which is an important mechanism that leads to cell death," said Gmeiner.

Knowing more about how the agent works means that doctors could combine it with other drugs to reach multiple treatment targets. For example, FdUMP[10] could possibly be used in combination with drugs that employ other mechanisms to kill cells.

"We may be able to combine it with other treatments for greater effectiveness," said Gmeiner. "There are likely novel combinations that we wouldn't have envisioned before this study."

Knowing more how the compound works would also allow scientists to monitor its effectiveness during treatment. Gmeiner said that if the compound continues to show promise in the laboratory, it could be tested in humans within a few years. The compound is licensed to AVI, a biopharmaceutical company.

Gmeiner's co-researchers are Zhi-Yong Liao¬, Ph.D., Olivier Sordet, Ph.D., Hong-Liang Zhang, Ph.D., Glenda Kohlhagen, Ph.D., Smitha Antony, Ph.D., and Yves Pommier, M.D., Ph.D., all with the National Cancer Institute at the time of the research.

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