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New Approach To Multidrug Resistance

Dartmouth researchers have found a way to dramatically restore the effectiveness of chemotherapy in cancer cells that have become resistant to its effects. The technique temporarily inhibits production of a prime protective mechanism used by tumors -- a molecular pump called P-glycoprotein that flushes drugs out of cells. The study, conducted by Associate Professor of Pharmacology and Toxicology Joshua Hamilton at Dartmouth Medical School, with colleagues from the medical school and the Norris Cotton Cancer Center, is reported in the current issue of Clinical Cancer Research.

One of the greatest obstacles to successful cancer treatment is the development of multidrug resistance by tumors -- that is, tumors become better able to withstand the actions of a wide variety of unrelated chemicals. The anti-drug pump is a major tool in multidrug resistance.

The researchers have found a novel way to suppress production of the pump long enough for cancer drugs to work.

Therapies for cancer treatment often use chemicals that impair the genetic machinery of cells. In previous studies, the Dartmouth researchers found that relatively low doses of these DNA-damaging drugs affect genes selectively. Genes active in day-to-day housekeeping -- for example, those involved in cell structure or basic food metabolism -- are less vulnerable to damage than genes induced in response to external signals -- such as hormone fluctuations or an incursion of foreign chemicals. Because the gene for P-glycoprotein is inducible, activated by cues from its environment, investigators were interested in how it would be affected by cancer chemotherapy drugs. They focused initially on one group of drugs called DNA cross-linking agents, which damage genes by fusing strands of their DNA together.

The researchers treated drug-resistant cells with a low dose of the cancer drug mitomycin C, waited 24 hours, then administered a second chemother
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Contact: Nancy Serrell
nancy.serrell@dartmouth.edu
603/650-3661
Dartmouth Medical School
13-Aug-1997


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