Compounds for preventing multidrug resistance in cancer cells containing the protein kinase inhibitor

摘要

This invention is directed to methods for preventing the emergence of multidrug resistance in tumor cells during cancer chemotherapy. In particular, it relates to the use of protein kinase inhibitors to prevent the induction of expression of the multidrug resistance gene (MDR1) encoding P-glycoprotein by chemotherapeutic drugs. MDR1 expression, which results in tumor cell resistance to subsequent treatment with certain chemotherapeutic drugs, is shown herein to be induced in response to treatment with various cytotoxic agents, including such agents that are and are not substrates for P-glycoprotein-mediated efflux from cancer cells. Inhibitors of protein kinases, in particular, protein kinase C, are shown herein to suppress this cellular response. In addition, such protein kinase inhibitors are also shown herein to inhibit expression of a gene encoding a multidrug resistance-associated protein (the MRP gene). The instant invention provides methods for using such protein kinase inhibitors to both suppress induction of MDR1 gene expression by cytotoxic drugs, and to inhibit expression of MRP. The invention also provides methods for identifying protein kinase inhibitors that have either or both of these effects on MDR1 and MRP expression. Thus, the invention provides useful methods and reagents for preventing the emergence of multidrug resistance in tumor cells treated with cytotoxic and chemotherapeutic drugs in cancer patients undergoing chemotherapy, when such protein kinase inhibitors are administered prior to or simultaneous with cytotoxic drug treatment in such individuals.