ジヒドロピリジン誘導体による多剤耐性の克服 Overcoming drug resistance in cancer cells with dihydropyridine analogues ジヒドロピリジン ユウドウタイ ニヨル タザイ タイセイ ノ コクフク

博士論文

Ten synthetic dihydropyridine analogues were investigated for their ability to reverse drug-resistance in a multidrug-resistant human carcinoma cell line, KB-Cl. Four dihydropyridine analogues completely reversed the resistance, 3 lowered the resistance and 3 had little effect. The radioactive photoactive dihydropyridine calcium channel blocker, [^3H] azidopine, photolabels P-glycoprotein in membrane vesicles from KB-Cl cells. This photolabeling was almost completely inhibited by excess dihydropyridine analogues that reversed or lowered drug-resistance. In contrast， the labeling was not significantly inhibited by analogues that do not reverse resistance. Among other reversing agents, cepharanthine and reserpine inhibited the [^3H] azidopine photolabeling, but thioridazine did not. SDB-ethylenediamine slightly inhibited the labeling at 100μM. An anticancer agent, vinblastine also inhibited the labeling. The correlation between the reversing of the drug-resistance and the inhibition of the [^3H] azidopin photolabeling of P-glycoprotein by dihydropyridine analogues suggests a role for P-glycoprotein in multidrug-resist ance and also the reversing of the resistance by dihydropyridine analogues.

医歯学総合研究科博士論文(医学) ; 学位取得日: 平成2年4月25日