Jiang X R, Kelsey S M, Wu Y L, Newland A C
Department of Haematology, London Hospital Medical College.
Br J Haematol. 1995 Jun;90(2):375-83. doi: 10.1111/j.1365-2141.1995.tb05162.x.
Cyclosporin A (CSA) exhibits greater multidrug resistance (MDR) modulating activity in vitro than other MDR modulators such as verapamil and quinidine. However, the immunosuppressive and nephrotoxic effects of CSA may limit its clinical use. PSC 833, a new cyclosporin D derivative, exerts a higher MDR reversal activity but lacks toxic or immunosuppressive effects. The drug-resistant sublines K/DAU100, K/DAU200, K/DAU300, K/DAU400, K/DAU500 and K/DAU600 have been derived from the drug-sensitive parental cell line, K562 cl.6 and CEM/VLB100 is a drug-resistant derivative of CCRF-CEM. We report a comparison of the effects of PSC 833 and CSA on daunorubicin (DAU) transport kinetics and chemosensitivity in these cell lines. Both CEM/VBL100 and K562 cl.6 DAU-resistant cells displayed high levels of P-glycoprotein (PGP), decreased DAU accumulation and increased DAU efflux when compared to their parental cells. PSC 833 was 1.6-, 3.4-, 4.9- and 4.6-fold more effective than CSA in reversing DAU resistance in higher resistance CEM/VLB100, K/DAU400, K/DAU500 and K/DAU600 cells respectively. DAU transport kinetics showed that PSC 833 was more effective than CSA in increasing cellular DAU accumulation and decreasing DAU efflux in higher resistant leukaemia subclones. PSC 833 could restore DAU retention at lower doses and was more active than CSA in all the resistant cells. A 89-100% restoration of intracellular DAU retention were gained by PSC 833 at 1.0 microM in K562 cl.6 DAU-resistant sublines, whereas a 73-100% restoration of DAU retention was obtained by CSA only at 30.0 microM in the same resistant sublines. PSC 833 at 3.0 microM is sufficient to restore full DAU retention in all resistant cells. CSA, however, even at 30.0 microM, cannot confer full restoration of DAU retention in higher resistance K562 cl.6/DAU sublines. By measuring MDR modulator-mediated short-term inhibition of PGP function, PSC 833 was found to be at least 10-30 times more active than CSA. As no effect on DAU retention and sensitivity has been found in sensitive parental cells with PSC 833, it is suggested that PSC 833 may act by blocking the effluxing function of PGP in the resistant leukaemia cells.
环孢素A（CSA）在体外比其他多药耐药（MDR）调节剂（如维拉帕米和奎尼丁）表现出更强的MDR调节活性。然而，CSA的免疫抑制和肾毒性作用可能会限制其临床应用。PSC 833是一种新的环孢素D衍生物，具有更高的MDR逆转活性，但没有毒性或免疫抑制作用。耐药亚系K/DAU100、K/DAU200、K/DAU300、K/DAU400、K/DAU500和K/DAU600源自药物敏感的亲本细胞系K562 cl.6，而CEM/VLB100是CCRF-CEM的耐药衍生物。我们报告了PSC 833和CSA对这些细胞系中柔红霉素（DAU）转运动力学和化学敏感性影响的比较。与它们的亲本细胞相比，CEM/VBL100和K562 cl.6 DAU耐药细胞均显示出高水平的P-糖蛋白（PGP），DAU积累减少，DAU外排增加。在逆转更高耐药性的CEM/VLB100、K/DAU400、K/DAU500和K/DAU600细胞中的DAU耐药性方面，PSC 833分别比CSA有效1.6倍、3.4倍、4.9倍和4.6倍。DAU转运动力学表明，在更高耐药性的白血病亚克隆中，PSC 833在增加细胞内DAU积累和减少DAU外排方面比CSA更有效。PSC 833可以在较低剂量下恢复DAU保留，并且在所有耐药细胞中比CSA更具活性。在K562 cl.6 DAU耐药亚系中，1.0 microM的PSC 833可使细胞内DAU保留恢复89 - 100%，而在相同耐药亚系中仅30.0 microM的CSA才能使DAU保留恢复73 - 100%。3.0 microM的PSC 833足以在所有耐药细胞中完全恢复DAU保留。然而，即使在30.0 microM时，CSA也不能在更高耐药性的K562 cl.6/DAU亚系中完全恢复DAU保留。通过测量MDR调节剂介导的PGP功能的短期抑制，发现PSC 833的活性至少比CSA高10 - 30倍。由于在敏感的亲本细胞中未发现PSC 833对DAU保留和敏感性有影响，因此提示PSC 833可能通过阻断耐药白血病细胞中PGP的外排功能发挥作用。
