Photoaffinity analogs for multidrug resistance-related transporters and their use in identifying chemosensitizers.
A major obstacle in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. The hallmark of this multidrug resistance (MDR) is overexpression of the MDR 1 P-glycoprotein or the multidrug resistance protein MRP1. It is well documented that these proteins confer MDR in cancer cells. Much evidence indicates that control of intracellular drug levels in MDR cells is determined by P-glycoprotein or MRP, and therefore these proteins are suitable targets for identifying MDR-reversing agents (MDR modulators). We originally explored the drug-binding ability of P-glycoprotein by synthesizing and using radioactive photoaffinity analogs of vinblastine. Since our initial discovery that P-glycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein- and MRP-specific photoaffinity analogs have been developed. In this review, photoaffinity analogs which specifically bind to P-glycoprotein or MRP are discussed. Moreover, utilizing these photoprobes to identify, characterize and localize the drug binding sites of P-glycoprotein and MRP is described. Using P-glycoprotein-specific photoaffinity analogs in combination with site-directed antibodies to several domains of this protein has allowed the localization of the general binding domains of some of the cytotoxic agents an MDR modulators on P-glycoprotein. However, the molecular architecture of the drug binding sites, their exact location on the P-glycoprotein molecule, and the total number of the drug binding sites remain to be determined. This review discusses recent advances in delineating the structure of the drug-binding sites of P-glycoprotein. Moreover, novel MRP1 photoaffinity analogs are reviewed. Copyright 1999 Harcourt Publishers Ltd.
Safa
Ahmad R.
AR
Indiana University Cancer Research Institute, 1044 West Walnut, Indianapolis, IN, 46202, USA