Meador J, Sweet P, Stupecky M, Wetzel M, Murray S, Gupta S, Slater L
Department of Medicine, College of Medicine, University of California, Irvine 92717.
Cancer Res. 1987 Dec 1;47(23):6216-9.
Cyclosporin A abrogates pleiotropic drug resistance in certain experimental tumors. Its impact on drug-sensitive tumors has not been investigated. Our studies show that in drug-sensitive Ehrlich ascites carcinoma and hepatoma 129 cyclosporin A enhances daunorubicin inhibition of DNA synthesis in vitro and prolongs survival of host mice in vivo. Of particular interest is that cyclosporin A converts ineffective daunorubicin regimens into those which result in prolongation of host mice survival. Other agents known to reverse pleiotropic drug resistance are reported to exert their effects by increasing intracellular drug accumulation. In contrast, our studies of drug transport in drug-sensitive Ehrlich ascites carcinoma and hepatoma 129 show that cyclosporin A causes minimal enhancement of [3H]daunorubicin uptake without inhibition of [3H]daunorubicin efflux in both the presence and absence of interrupted active daunorubicin efflux. This suggests that the mechanism of action of daunorubicin enhancement by cyclosporin A in drug-sensitive tumors is not simply the result of increased intracellular daunorubicin accumulation. In vivo dosages of cyclosporin A in the current study are comparable to those which can be used with reasonable safety in humans. We conclude that cyclosporin A may be useful in the potentiation of anthracycline antibiotic therapy directed against drug-sensitive as well as drug-resistant tumors.
环孢素A可消除某些实验性肿瘤中的多药耐药性。其对药物敏感肿瘤的影响尚未得到研究。我们的研究表明，在药物敏感的艾氏腹水癌和肝癌129中，环孢素A在体外增强柔红霉素对DNA合成的抑制作用，并在体内延长宿主小鼠的存活时间。特别值得关注的是，环孢素A可将无效的柔红霉素治疗方案转变为能延长宿主小鼠存活时间的方案。据报道，其他已知可逆转多药耐药性的药物是通过增加细胞内药物蓄积来发挥作用的。相比之下，我们对药物敏感的艾氏腹水癌和肝癌129中药物转运的研究表明，无论是否存在被阻断的柔红霉素主动外排，环孢素A在最小程度增强[3H]柔红霉素摄取的同时，并不抑制[3H]柔红霉素的外排。这表明环孢素A在药物敏感肿瘤中增强柔红霉素作用的机制并非仅仅是细胞内柔红霉素蓄积增加的结果。本研究中环孢素A的体内剂量与可在人体安全使用的剂量相当。我们得出结论，环孢素A可能有助于增强针对药物敏感肿瘤以及耐药肿瘤的蒽环类抗生素治疗效果。
