The focus of the Molecular Therapeutics Section in on the development of strategies to prevent or reverse the development of drug resistance. We seek basic science approaches to this problem which will lead directly to improved antineoplastic therapy in the clinic. We have studied P- glycoprotein most extensively in the past, characterizing regulation of expression and function. Currently the majority of work on P-glycoprotein is done in conjunction with clinical studies. We have examined the expression of P-glycoprotein in human tumor samples, seeking correlations between expression, clinical resistance, and reversal of resistance. The clinical studies have included patients with lymphoma, breast cancer, and renal cell carcinoma. Phase I studies of PSC 833 in combination vinblastine or paclitaxel are ongoing. Basic science efforts in the laboratory are centered principally on non-P-glycoprotein mediated mechanisms of resistance. We have explored the contribution of growth factor pathways and cell survival pathways to resistance in breast cancer. While such mechanisms cannot provide the very high levels of resistance that P-glycoprotein can, they may be more important in primary malignancies in determining the intrinsic sensitivity of that tumor to therapy and may provide a target for the prevention of resistance. Efforts are ongoing to identify a novel drug transporter in a human breast cancer subline. The cells have no expression of, but do have drug efflux similar to that observed with P-glycoprotein. We have begun expression cloning as a strategy for identifying this putative transporter gene. Finally, The laboratory is involved in extensive collaborations with investigators in the Developmental Therapeutics Program to explore novel approaches to the identification of new anticancer agents in the NC drug screen.