Chemoprotection of hematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multidrug-resistant cancers

Cancers are frequently chemoresistant because of overexpression of P-glycop rotein, Two different approaches to improve cancer treatment are currently being investigated in clinical trials: inhibition of P-glycoprotein functio n by reversing agents, and alleviation of leukocytopenia by MDR1 gene trans fer to normal bone marrow of patients, We report here that retroviral vecto rs encoding a mutant P-glycoprotein (MDR1-F983A) protect hematopoietic cell s from anticancer drugs even in the presence of trans-(E)-flupentixol, an i nhibitor of P-glycoprotein, Transfer of either mutant or wild-type MDR1 to K562 erythroleukemia cells or primary murine bone marrow resulted in reduce d accumulation of daunomycin and vinblastine because of increased drug effl ux. trans-(E)-Flupentixol at concentrations up to 10 mu M failed to reverse drug efflux mediated by the product of the mutant MDR1 while wild-type P-g lycoprotein was inhibited. In the presence of 2 mu M trans-(E)-flupentixol chemoresistance to daunomycin was circumvented only in K562 cells transduce d with wild-type, but not with mutant, MDR1, Moreover, drug resistance of K B-8-5 epidermoid cancer cells, which express the wildtype MDR1 gene at leve ls comparable to clinical specimens from multidrug-resistant cancers, was f ully overcome in the presence of trans-(E)-flupentixol. Vectors expressing mutant P-glycoprotein may help improve chemotherapy by allowing safe dose i ntensification under conditions in which multidrug-resistant cancers are re ndered drug sensitive by reversing agents.