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Possible New Approach to Preventing Chemotherapy Drug Resistance

Possible New Approach to Preventing Chemotherapy Drug Resistance

Researchers at the Howard Hughes Medical Institute at Duke University Medical Center have shown how drugs that stop organ transplant rejection also partially reverse drug resistance in certain cancer cells.

Such resistance, which thwarts cancer chemotherapy, is a principal cause of death for cancer patients. The scientists have identified a new target to stop drug resistance in cancer cells. The researchers believe the finding will help scientists develop new compounds to prevent drug resistance in patients with cancer, but without compromising the immune system.

"We may have identified an Achilles' heel in the body's natural reaction in expelling toxic drugs," said geneticist Dr. Joseph Heitman, the study's principal investigator.

The research was supported, in part, by the National Institute of Environmental Health Sciences and a Rhone Poulenc Rorer Hematology Scholar award to Heitman's colleague Dr. Charles Hemenway.

Heitman and Hemenway, both researchers in Duke's Comprehensive Cancer Center, reported their findings in the August 2nd issue of the Journal of Biological Chemistry. They found that three drugs given to stop organ transplant rejection--cyclosporine (Sandimmune), FK506, and rapamycin--also block the cellular pump that expels cancer chemotherapy drugs. But the drugs block the pump by different mechanisms.

Antirejection Drugs Prevent Resistance via Different Mechanisms

Previously, scientists believed the antirejection drugs acted like sludge in a gas tank, clogging the pump mechanism. But the Duke scientists showed that FK506 and rapamycin also tie up a separate protein, called FKBP12, which they showed is an essential activator for the pump to work correctly. In other words, the two drugs primarily halt the cellular pump by removing a vital part, like a valve from a car's fuel pump.

"Cyclosporin-related drugs are now being tested for their ability to reverse chemotherapy resistance in cancer patients, but little had been known about how these common immune suppressants work in this setting," Heitman said. "Our findings shed light on a new mechanism that can be exploited to overcome drug resistance in cancer cells."

The researchers tested their ideas using common baker's yeast as a model organism, because basically the same multidrug resistance pump (MDR) is found in yeast, animals, and people, Heitman said.

The MDR pump is a large protein that acts like a pore in the cell surface. It selectively pumps out toxic chemicals that find their way inside the cell. Normally, the MDR pump protects the cell against poisons, but resistant cancer cells have many times the normal amount of MDR protein to protect them from chemotherapy drugs. These cells work overtime, expelling chemotherapy drugs that would normally kill a cancerous tumor and allowing runaway cell growth to continue. Physicians and researchers have been searching for ways to clog the MDR pump for many years. But many promising MDR blockers have turned out to be toxic in the doses needed for them to be effective.

"The MDR protein is so big that its FKBP12 component is like a flea on an elephant's back," said Heitman. "But it appears to be crucial. Based on our experiments, we think FKBP12 could help open and close the pump. When FKBP12 is missing, the pump may not be able to open and close properly to expel the drugs from the cell."

The researchers say the findings could change the way doctors evaluate potential MDR-blocking drugs. Such drugs would be similar in shape to FK506 and rapamycin but without their suppressant effects on the immune system. Heitman says such compounds have already been found but have not yet been tested in people.

"It may be that non-immunosuppressive compounds that block FKBP12 will turn out to be better at overcoming drug resistance in tumor cells," Heitman said. "Simply jamming the pump mechanism may not be enough."

 
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