CSHL scientists correlate enzyme expression levels with chemotherapy dru...( Why do cancer patients develop resis...),Health

Why do cancer patients develop resistance to chemotherapy drugs, sometimes abruptly, after a period in which the drugs seem to be working well to reduce tumors or hold them in check? Although largely a mystery to scientists, the result when this occurs is all too familiar: patients relapse and in many cases die when their cancers become resistant.

A team of researchers at Cold Spring Harbor Laboratory (CSHL), seeking to understand the genetic underpinnings of cancer therapy response, have identified what they regard a "significant contributor to resistance." Using a novel screening technique involving "pools" of gene-regulating short RNA molecules, they were able to determine how resistance to a drug called doxorubicin arises in lymphomas occurring in a particular strain of mice.

"The method we developed is notable," said CSHL Professor Scott W. Lowe, Ph.D., a leader of the research team, "because it gives us a view of how resistance works at the level of individual molecules in living animals, and also because it can be easily extended to other chemotherapy drugs and tumor systems to give a potentially global view of factors that mediate response to cancer therapy."

Many genetic factors are already known to influence the effectiveness of anti-cancer drugs. Such factors manifest themselves in a variety of ways, some of them remarkable. One known gene change, for instance, results in increased expression of pump-like mechanisms that remove chemotherapeutic toxins from cancer cells; another causes changes in cellular structure that prevent drug molecules from "docking" with their targets.

The research by the CSHL team, which included Professors W. Richard McCombie, Ph.D., and Gregory J. Hannon, Ph.D., in addition to Dr. Lowe, demonstrated the mechanism of one form of resistance in cell culture and living mice. These results were reported in Proce
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