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Dartmouth Medical School Dartmouth-Hitchcock Medical Center


Is cancer combo too effective?

By Amos Esty

Eastman, a professor of pharmacology and toxicology, has been at DMS since 1989.

A test that pitted two drugs against leukemia cells produced some promising results—perhaps too promising, cautions lead researcher Alan Eastman, Ph.D. He has long been interested in the dynamics that lead to the death of cells, particularly cancer cells. Several years ago, he and other researchers in his lab were examining the drug vinblastine when they discovered something new. Eastman says it was well established that vinblastine interferes with the process of cell division and can eventually kill leukemia cells, a process that can take up to about 24 hours. "Everybody has accepted that as a mechanism of action for this family of drugs," he says. "They're highly potent and they're used in cancer chemotherapy."

But when Eastman suppressed a family of proteins—called Bcl-2 proteins—that can prevent the death of cells, vinblastine was able to kill cells within just a few hours. That finding led Eastman to wonder whether combining a drug that inhibits Bcl-2 proteins with vinblastine would be an effective treatment against leukemia. So he tested a combination of dinaciclib (a drug that suppresses specific Bcl-2 proteins) and vinblastine on leukemia cell lines from about 40 patients. As he reported in Cancer Biology and Therapy, the combination killed every leukemia cell in most cell lines within about four hours.

But the success comes with a caveat, says Eastman. "The downside is it's almost too effective." The problem, he explains, is that a drug that's so widely effective may be more apt to kill normal cells as well, whereas a drug that kills only a few cell lines may be targeting a specific vulnerability perhaps not present in normal cells.

Safe: Yet so far, the combination appears to be safe. When normal white blood cells were exposed to the drugs, there was no greater cell death than expected, and Eastman says previous clinical trials using dinaciclib have shown that patients can tolerate the drug. With these results in hand, he hopes to move forward with clinical trials. "I think it has some real potential for therapy," he says, even though, he emphasizes, there is still much left to be learned.

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