GENERATION OF A DRUG-RESISTANCE PROFILE BY QUANTITATION OF MDR-1 P-GLYCOPROTEIN IN THE CELL-LINES OF THE NATIONAL-CANCER-INSTITUTE ANTICANCER DRUG SCREEN/

Identifying new chemotherapeutic agents and characterizing mechanisms of resistance may improve cancer treatment. The Anticancer Drug Screen of the National Cancer Institute uses 60 cell lines to identify new a gents. Expression of mdr-1/P-glycoprotein was measured by quantitative PCR. Expression was detected in 39 cell lines; the highest levels wer e in renal and colon carcinomas. Expression was also detected in all m elanomas and central nervous system tumors, but in only one ovarian ca rcinoma and one leukemia cell line. Using a modified version of the CO MPARE program, a high correlation was found between expression of mdr- l and cellular resistance to a large number of compounds. Evidence tha t these compounds are P-glycoprotein substrates includes: (a) enhancem ent of cytotoxicity by verapamil; (b) demonstration of cross-resistanc e in a multidrug-resistant cell line, (c) ability to antagonize P-glyc oprotein, increasing vinblastine accumulation by decreasing efflux; an d (d) inhibition of photoaffinity labeling by azidopine. Identificatio n of many heretofore unrecognized compounds as substrates indicates th at P-glycoprotein has a broader substrate specificity than previously recognized. This study confirms the validity of this novel approach an d provides the basis for similar studies examining a diverse group of gene products, including other resistance mechanisms, putative drug ta rgets, and genes involved in the cell cycle and apoptosis.