GENETIC ANALYSIS OF THE MULTIPLE DRUG RESISTANCE PHENOTYPE IN TUMOR CELLS

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Resistance to multiple drugs is a major impediment to the successful chemotherapy of human cancers. To investigate the genetic and biochemical basis for this multidrug resistance (MDR) phenotype, we have developed a model system using the cultured KB cell, a human carcinoma cell line selected independently for resistance to high levels of either colchicine, adriamycin or vinblastine which is cross-resistant to colchicine, adriamycin, vincristine, vinblastine, puromycin, and actinomycin D. This resistance results from expression of the MDR1 gene which encodes a 170,000 dalton membrane glycoprotein (P-glycoprotein) which is a multidrug transport protein. ATP-dependent transport of vinblastine has been demonstrated using membrane vesicles from MDR cells. Expression vectors into which the MDR1 cDNA are cloned confer the complete MOR phenotype on drug-sensitive cells, as does a retrovirus carrying the MDR1 gene. Expression of MDR1 RNA and P-glycoprotein occurs in normal kidney, liver, colon, and adrenal and in tumors derived from these tissues which are intrinsically resistant to chemotherapy as well as several other tumors. Acquired drug-resistance in childhood leukemia, neuroblastoma, rhabdomyosarcoma and in pheochromocytoma may be associated with increased MDR1 RNA levels.