Current cancer chemotherapy programs often provide temporary clinical improvement; however, tumors which survive the initial therapeutic attack often recover with increased resistance to many structurally unrelated drugs. This phenomenon is termed multidrug resistance (MDR), and is often mediated by increased expression of proteins which act as drug efflux pumps, such as P-glycoprotein and MRP. It is believed that compounds which antagonize these pumps could be used to impair the expansion of MDR cells, and so would be of enormous therapeutic value. Unfortunately, no compounds have yet proven to have clinical utility as MDR reversing agents. The overall goal of this project is to identify and characterize new compounds which are able to selectively overcome MDR. The applicant's studies have identified several new natural products and synthetic compounds that circumvent transporter-mediated multiple drug resistance in vitro. These studies have also led the generation of the hypothesis that selectivity of antagonism toward either P-glycoprotein or MRP is highly desirable for new clinical agents. Studies described herein will seek to maximize this selectivity through computer-aided design of novel anti-MDR compounds. Further assessment of the potential clinical utility of these compounds depends on in vivo testing in animal models of MDR. To attempt to mimic the clinical situation, the applicant will use xenografts of P-glycoprotein- and MRP-overexpressing cells in mice, and to determine the abilities of these agents to selectively reverse MDR in vivo. When appropriate, the mechanism of reversal will be explored by examination of the pharmacokinetics and disposition of the modulators and selected anticancer drugs. These studies should allow a critical evaluation of the potential utility of these novel compounds as clinical agents.
