Amplification of the gene encoding multidrug resistance-associated protein (MRP) and overexpression of its cognate mRNA have been detected in multidrug-resistant cell lines derived from several different tumor types. To establish whether or not the increase in MRP is responsible for drug resistance in these cell lines, we have transfected HeLa cells with MRP expression vectors. The transfectants display an increase in resistance to doxorubicin that is proportional to the levels of a Mr 190,000, integral membrane protein recognized by anti-MRP antibodies. The transfectants are also resistant to vincristine and VP-16 but not to cisplatin. The results demonstrate that MRP overexpression confers a multidrug resistance phenotype similar to that formerly associated exclusively with elevated levels of P-glycoprotein.
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This work was supported by grants from the Medical Research Council of Canada and the Cancer Research Society (S. P. C. C. and R. G. D.). C. E. G. is a recipient of a Medical Research Council postdoctoral fellowship; D. R. H. is the recipient of a Queen's University graduate award; and G. V. and K. C. A. were supported by the Ontario Cancer Treatment and Research Foundation. S. P. C. C. is a Career Scientist of the Ontario Cancer Treatment and Research Foundation, and R. G. D. is the Stauffer Research Professor of Queen's University.