Ar. Safa, Photoaffinity analogs for multidrug resistance-related transporters and their use in identifying chemosensitizers, DRUG RESIST, 2(6), 1999, pp. 371-381
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.