Michieli M, Damiani D, Michelutti A, Melli C, Ermacora A, Geromin A, Fanin R, Russo D, Baccarani M
Department of Clinical and Morphological Research, University Hospital, Udine, Italy.
Haematologica. 1996 Jul-Aug;81(4):295-301.
The results obtained so far in studies designed to neutralize P glycoprotein (PGP)-related multidrug resistance (MDR) by using MDR reversal agents, have not yet fulfilled the promise of the experiments which were performed in vitro. In order to improve PGP-related MDR neutralization, we tested in vitro the activity of the cyclosporine derivative SDZ PSC 833 (PSC) together with doxorubicin (DOX) and with two new DOX derivatives named 4' iodo 4' deoxy-doxorubicin (IODODOX) and methoxy-morpholynil-doxorubicin (MMDOX, FCE 23762) using four different human cell lines and their multi-drug resistant variants.
Anthracycline toxicity was evaluated by using the MTT method after a 7-day culture with continuous exposure to the antitumor drugs with or without the addition of PSC.
PSC significantly downmodulated the toxicity of all three anthracyclines in all the four cell systems. However, despite the great increase caused by PSC in the toxicity of DOX and a more modest effect on the toxicity of the two DOX derivatives, this MDR reversal agent could only completely block the PGP mediated MMDOX resistance whereas DOX refractoriness was only decreased.
The combination of MMDOX or IODODOX with PSC 1.6 microM is more efficient than the combination of DOX plus PSC for the full reversion of PGP-mediated drug resistance. Careful clinical studies are required to evaluate if these associations can also effectively and safely neutralize MDR in vivo.
迄今为止，旨在通过使用多药耐药逆转剂来中和P糖蛋白（PGP）相关的多药耐药性（MDR）的研究结果，尚未实现体外实验所预期的效果。为了改善与PGP相关的MDR中和效果，我们使用四种不同的人类细胞系及其多药耐药变体，在体外测试了环孢素衍生物SDZ PSC 833（PSC）与阿霉素（DOX）以及两种名为4'碘-4'脱氧阿霉素（IODODOX）和甲氧基-吗啉代-阿霉素（MMDOX，FCE 23762）的新型DOX衍生物的活性。
在持续暴露于抗肿瘤药物（添加或不添加PSC）的情况下培养7天后，使用MTT法评估蒽环类药物的毒性。
PSC在所有四个细胞系统中均显著下调了所有三种蒽环类药物的毒性。然而，尽管PSC使DOX的毒性大幅增加，对两种DOX衍生物的毒性影响较小，但这种MDR逆转剂只能完全阻断PGP介导的MMDOX耐药性，而DOX难治性仅有所降低。
MMDOX或IODODOX与1.6微摩尔PSC联合使用，在完全逆转PGP介导的耐药性方面比DOX加PSC联合使用更有效。需要进行仔细的临床研究，以评估这些联合用药在体内是否也能有效且安全地中和MDR。
