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 mu ltiple chemotherapeutic agents in tumor cells,The hallmark of this multidru g resistance (MDR) is overexpression of the MDR I P-glycoprotein or the mul tidrug resistance protein MRPI. It is well documented that these proteins c onfer MDR in cancer cells. Much evidence indicates that control of intracel lular 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 o f P-glycoprotein by synthesizing and using radioactive photoaffinity analog s of vinblastine. Since our initial discovery that P-glycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein- and MRP-specific ph otoaffinity analogs have been developed. In this review, photoaffinity anal ogs which specifically bind to P-glycoprotein or MRP are discussed. Moreove r, utilizing these photoprobes to identify, characterize and localize the d rug binding sites of P-glycoprotein and MRP is described. Using P-glycoprot ein-specific photoaffinity analogs in combination with site-directed antibo dies 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 n umber of the drug binding sites remain to be determined. This review discus ses recent advances in delineating the structure of the drug-binding sites of P-glycoprotein. Moreover, novel MRPI photoaffinity analogs are reviewed. (C) 1999 Harcourt Publishers Ltd.