Why and wherefores of drug resistance.

Whys and wherefores of drug resistance

To make a bad situation worse, cancer cells may be inherently resistant to one or more drugs, or become resistant after drug treatment begins. Proposed mechanisms for such drug resistance include gene amplification, where multiple copies of key genes are made by the cancer cell as protection, and the presence of a cellular protein called P-glycoprotein, or P-170 (SN: 1/3/87, p.12). Scientists recently reported progress in understanding these mechanisms, as well as in the use of other drugs that can reverse a tumor's ability to survive chemothrapy.

After discovering P-170 in the mid-1970s, scientists noted that presence of the human MDR1 gene coding for the protein can confer multidrug resistance. Since that time, scientists at the National Cancer Institute (NCI) in Bethesda, Md., and elsewhere have cloned the gene and studied its protein product. P-170, which loops through the cell membrane (see drawing), apparently acts as a pump, pushing drugs out of a cell, says NCI's Michael M. Gottesman. He and his co-workers now have devised a theoretical model of how such a pump might work. In recent laboratory studies, they also found the pump is active in certain normal cells, possibly to remove plant toxins ingested in food. How the protein's presence in normal cells will impinge on research efforts to stop its activity in cancer cells is unclear, Gottesman says. "I don't think that problem is overwhelming, but we're not nearly ready for clinical trials [of new drugs that stop the P-170 pump]," he adds.

Scientists have looked at the well-known pump-blocking drug verapamil as a way to reverse drug resistance (SN:4/13/85, p.237). At Long Beach (Calif.) Veterans Administration Medical Center, researchers report using verapamil and another pump blocker called lidocaine in combination with anticancer agents. Of five volunteers with drug-resistant, growing malignancies, three patients had partial remission, while tumors in the other patients stabilized. But because these agents lower blood pressure, researchers are seeking less toxic approaches. Among these are the recently developed drugs buthionine sulfoximine and aphidicolin, for which U.S. clinical trials are being designed, according to NCI's Robert F. Ozols. By inhibiting a specific enzyme, buthionine sulfoximine reduces the levels of a peptide called glutathione. Ozols says glutathione seems to be important in the development of multidrug resistance, because it is found in high levels in resistant cells. Aphidicolin, on the other hand, halts DNA repair, one mechanism used by resistant cells to recovr from drug treatment.

While the presence of P-170 can cause a treatment dilemma, NCI's Bruce Chabner says scientists have developed laboratory screening tests that exploit the protein to identify agents against drug-resistant cells. And other researchers at NCI, the Mayo Clinic in Rochester, Minn., and Hospital Saint-Luc in Montreal recently isolated a DNA probe that identifies a glutathione-related enzyme, one they predict will be used as a marker to detect precancerous changes in cells. A report in the May 20 CELL says a change in just one of the 1,280 amino acids in P-170 can make a cell more drug resistant. That study, from the University of Illinois in Chicago and Cetus Corp. in emeryville, Calif., supports the idea that gene therapy may someday make cancer cells more drug-sensitive and healthy cells more tolerant of toxic drugs.