Possible New Approach to Preventing Chemotherapy Drug Resistance

Researchers at the Howard Hughes Medical Institute at Duke UniversityMedical Center have shown how drugs that stop organ transplantrejection also partially reverse drug resistance in certain cancercells.

Such resistance, which thwarts cancer chemotherapy, is a principalcause of death for cancer patients. The scientists have identifieda new target to stop drug resistance in cancer cells. The researchersbelieve the finding will help scientists develop new compoundsto prevent drug resistance in patients with cancer, but withoutcompromising the immune system.

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

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

Heitman and Hemenway, both researchers in Duke's ComprehensiveCancer Center, reported their findings in the August 2nd issueof the Journal of Biological Chemistry. They found that threedrugs given to stop organ transplant rejection--cyclosporine (Sandimmune),FK506, and rapamycin--also block the cellular pump that expelscancer chemotherapy drugs. But the drugs block the pump by differentmechanisms.

Antirejection Drugs Prevent Resistance via Different Mechanisms

Previously, scientists believed the antirejection drugs actedlike sludge in a gas tank, clogging the pump mechanism. But theDuke scientists showed that FK506 and rapamycin also tie up aseparate protein, called FKBP12, which they showed is an essentialactivator for the pump to work correctly. In other words, thetwo drugs primarily halt the cellular pump by removing a vitalpart, like a valve from a car's fuel pump.

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

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

The MDR pump is a large protein that acts like a pore in the cellsurface. It selectively pumps out toxic chemicals that find theirway inside the cell. Normally, the MDR pump protects the cellagainst poisons, but resistant cancer cells have many times thenormal amount of MDR protein to protect them from chemotherapydrugs. These cells work overtime, expelling chemotherapy drugsthat would normally kill a cancerous tumor and allowing runawaycell growth to continue. Physicians and researchers have beensearching for ways to clog the MDR pump for many years. But manypromising MDR blockers have turned out to be toxic in the dosesneeded for them to be effective.

"The MDR protein is so big that its FKBP12 component is likea flea on an elephant's back," said Heitman. "But itappears to be crucial. Based on our experiments, we think FKBP12could help open and close the pump. When FKBP12 is missing, thepump may not be able to open and close properly to expel the drugsfrom the cell."

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

"It may be that non-immunosuppressive compounds that blockFKBP12 will turn out to be better at overcoming drug resistancein tumor cells," Heitman said. "Simply jamming the pumpmechanism may not be enough."