title: [A molecular basis for multidrug resistance and reversal of the resistance].
abstract: Multidrug-resistance is frequently characterized by enhanced drug efflux resulting from a membrane glycoprotein of 170,000 daltons (P-glycoprotein). Analysis of cloned cDNAs for the human MDR 1 gene, whose product is the P-glycoprotein, indicates that P-glycoprotein is an energy-dependent drug-efflux system for cytotoxic hydrophobic anticancer drugs. We have demonstrated that a photoanalog of a reversing agent, SDB-ethylenediamine, specifically binds to P-glycoprotein. The binding site on P-glycoprotein seems to be identical with that of anticancer agents and other reversing agents. On the other hand, the radioactive photoactive dihydropyridine calcium channel blocker, [3H] azidopine, photolabels P-glycoprotein in membrane vesicles from multidrug-resistant cells. This photolabeling is almost completely inhibited by excess dihydropyridine analogs that reverse or lower drug-resistance. In contrast, the labeling is not significantly inhibited by analogs that do not reverse resistance. These results suggest that it may be possible to quickly screen for dihydropyridine analogs that reverse multidrug resistance by measuring the inhibition of [3H] azidopine labeling of P-glycoprotein.
authors.affiliation: Institute of Cancer Research, Kagoshima University.
authors.forename: S
authors.initials: S
authors.lastname: Akiyama
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
authors.forename: H
authors.initials: H
authors.lastname: Kikuchi
authors.forename: M
authors.initials: M
authors.lastname: Kamiwatari
authors.forename: Y
authors.initials: Y
authors.lastname: Nagata
authors.forename: K
authors.initials: K
authors.lastname: Seto
authors.forename: R
authors.initials: R
authors.lastname: Sakota
authors.forename: A
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: S
authors.initials: S
authors.lastname: Hanada
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001386:Azides / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; C041130:azidopine