Lehne G, De Angelis P, Clausen O P, Rugstad H E
Department of Clinical Pharmacology, National Hospital, Oslo, Norway.
Br J Cancer. 1996 Dec;74(11):1719-29. doi: 10.1038/bjc.1996.621.
Drug resistance is a major obstacle to successful chemotherapy of primary liver cancer, which is associated with high expression of the multidrug resistance (MDR) gene product P-glycoprotein (Pgp), a multidrug efflux transporter. The most effective single agents in treatment of primary liver carcinoma belong to the anthracycline family, yet several anthracyclines are known to be substrates for Pgp. In the present study, we compared four anthracyclines with respect to cell growth inhibition, intracellular accumulation and cellular efflux using the HB8065/R human hepatoma cell line which is rich in Pgp, and the Pgp-poor parental line HB8065/S. The anthracyclines were also administered in conjunction with the Pgp-modifying agents verapamil and SDZ PSC 833 to assess modulation of resistance. The HB8065/R cells were sensitive to aclarubicin (ACL) and highly resistant to epirubicin (EPI), doxorubicin (DOX) and daunorubicin (DNR). SDZ PSC 833 enhanced accumulation, decreased efflux and increased cytotoxicity of EPI, DOX and DNR in the HB8065/R cells, but none of these effects was seen with ACL. In conclusion, ACL is apparently not transported by Pgp and retains its activity in a multidrug-resistant human hepatoma cell line; such properties can be exploited for clinical purposes.
耐药性是原发性肝癌化疗成功的主要障碍，这与多药耐药（MDR）基因产物P-糖蛋白（Pgp，一种多药外排转运蛋白）的高表达有关。治疗原发性肝癌最有效的单一药物属于蒽环类药物，但已知几种蒽环类药物是Pgp的底物。在本研究中，我们使用富含Pgp的HB8065/R人肝癌细胞系和Pgp含量低的亲本细胞系HB8065/S，比较了四种蒽环类药物在细胞生长抑制、细胞内蓄积和细胞外排方面的差异。蒽环类药物还与Pgp修饰剂维拉帕米和SDZ PSC 833联合使用，以评估耐药性的调节情况。HB8065/R细胞对阿柔比星（ACL）敏感，对表柔比星（EPI）、多柔比星（DOX）和柔红霉素（DNR）高度耐药。SDZ PSC 833增强了EPI、DOX和DNR在HB8065/R细胞中的蓄积，降低了外排，并增加了细胞毒性，但ACL未出现这些效应。总之，ACL显然不是由Pgp转运的，并在多药耐药的人肝癌细胞系中保留其活性；这些特性可用于临床目的。
