Akiyama S, Yoshimura A, Kikuchi H, Kamiwatari M, Nagata Y, Seto K, Sakota R, Utsunomiya A, Hanada S, Hashimoto S
Institute of Cancer Research, Kagoshima University.
Gan To Kagaku Ryoho. 1989 Apr;16(4 Pt 2-1):1266-72.
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.
多药耐药性通常表现为一种170,000道尔顿的膜糖蛋白（P - 糖蛋白）导致的药物外排增强。对人类多药耐药1基因（其产物为P - 糖蛋白）的克隆cDNA进行分析表明，P - 糖蛋白是一种针对细胞毒性疏水抗癌药物的能量依赖性药物外排系统。我们已经证明，一种逆转剂SDB - 乙二胺的光类似物能特异性地与P - 糖蛋白结合。P - 糖蛋白上的结合位点似乎与抗癌药物及其他逆转剂的结合位点相同。另一方面，放射性光活性二氢吡啶钙通道阻滞剂[³H]叠氮平能对多药耐药细胞的膜囊泡中的P - 糖蛋白进行光标记。这种光标记几乎完全被能逆转或降低耐药性的过量二氢吡啶类似物所抑制。相比之下，不能逆转耐药性的类似物对标记的抑制作用不明显。这些结果表明，通过测量[³H]叠氮平对P - 糖蛋白标记的抑制作用，有可能快速筛选出能逆转多药耐药性的二氢吡啶类似物。
