Genetics of multidrug resistance: relationship of a cloned gene to the complete multidrug resistant phenotype.

Resistance to multiple chemotherapeutic agents remains the major cause of failure in cancer chemotherapy. Multidrug resistant cell lines developed in vitro have provided a useful model for analyzing this phenomenon. We describe a complementary DNA, lambda DR11, which is present in normal cells and overexpressed in multidrug resistant cell lines. We have placed this complementary DNA in an expression vector which uses the beta-actin promoter to drive transcription and introduced this vector via transfection into drug sensitive cells. Cells expressing increased levels of lambda DR11 are resistant to the same broad spectrum of chemotherapeutic agents which characterize the multidrug resistant phenotype. The expression of this complementary DNA in transfected clones is dependent upon the number of copies of lambda DR11 integrated in the genome as well as the amount of selective pressure placed on the clone during selection of the clone. Furthermore, the number of copies of lambda DR11 in the genome and the expression of lambda DR11 can be modulated by releasing an individual clone from selective pressure or by increasing the selective pressure on the clone. The endogenous sequences encoding the multidrug resistance gene are not amplified in transfected drug resistant clones. Finally, the drug resistant phenotype is reversed in the transfected clones by verapamil just as drug resistance is reversed in multidrug resistant cell lines.