GENETIC ANALYSIS OF THE MULTIPLE DRUG RESISTANCE PHENOTYPE IN TUMOR CELLS

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During the course of chemotherapy of human cancers, variants which are resistant to multiple drugs frequently arise. We have been investigation the genetic and biochemcial basis for this pleiotropic resistance of human tumor cells to chemotherapeutic agents. A model system using the cultured KB cell, a human carcinoma cell line, has been developed in which mutant cells selected independently for resistance to high levels of either colchicine, adriamycin or vinblastine have also been found to be cross-resistant to colchicine, adriamycin, vincristine, vinblastine, puromycin and actinomycin-D. Genetic linkage of these multiple drug resistances in the colchicine-selected line has been demonstrated by their coordiante appearance, coordinate reversion, codominance and cosegregation in somatic cell hybrids, and cotransfer by DNA-mediated gene transfer. Accumulation of several of the drugs involved in the multiple drug-resistance phenotype has been shown to be reduced in the KB cells. Drug-resistance correlates with the loss of a family of glycoproteins of molecular weights 70-80,000 on the cell surface detected by polyclonal and monoclonal antibodies and, in some cases, the appearance of a low molecular weight protein (p21). Drug-resistance also correlates with amplification of DNA segment detected either by an in gel renaturation technique or on Southern blots using probes cloned from amplified DNA in drug-resistant hamster cells.