Viladkar A, Chitnis M
Chemotherapy Division, Cancer Research Institute, Tata Memorial Centre, Parel, Bombay, India.
Cancer Biother. 1993 Spring;8(1):77-85. doi: 10.1089/cbr.1993.8.77.
Reserpine, the crystalline active substance isolated from the Rauvolfia plant, produces a characteristic vasodepressor effect in hypertensive patients. Apart from its antihypertensive property, reserpine also possesses transquillising and vasodepressor action, hence it is employed as supportive therapy in the treatment of cardiac disorders. Doxorubicin is a potent anticancer agent, the use of which is limited by its cumulative dose-dependent cardiotoxicity. Epirubicin is a derivative of doxorubicin having more favourable therapeutic index than doxorubicin and possessing less hematologic and cardiac toxicity at comparable doses. The data presented in this paper show the effect of reserpine as a chemosensitizer, when used in combination with epirubicin on P388 murine leukemia cells sensitive (P388/S) and resistant to doxorubicin (P388/DOX) cells. Inhibition of 3H-TdR incorporation into DNA was used as an index of the cytotoxic effects of drug when used alone or in combination. The combination of reserpine (1 microM) and epirubicin (1.7, 8.6 and 17.2 microM) indicated a significant enhancement in the DNA biosynthesis inhibition in P388/S and P388/DOX cell lines. The most prominent feature of the multidrug-resistant cell is the reduced accumulation of the drug intracellularly. P388/DOX cells showed less accumulation of epirubicin in the cell as compared to that of the parental cell line. Further studies demonstrated that reserpine significantly enhanced the intracellular accumulation of epirubicin in both the cell lines. The nature of DNA damage caused by the combination of reserpine and epirubicin was irreversible when studied in P388/DOX cell line. The combination of reserpine (5mg/kg) and epirubicin (1mg/kg) significantly potentiated the antitumor activity of epirubicin in P388/DOX tumor bearing mice. These studies suggest that reserpine can be used as an adjuvant in the cancer chemotherapy to potentiate the antiproliferative activity of anticancer drugs.
利血平是从萝芙木属植物中分离出的结晶性活性物质，可使高血压患者产生特征性的血管减压作用。除了其抗高血压特性外，利血平还具有镇静和血管减压作用，因此被用作心脏病治疗的辅助疗法。阿霉素是一种强效抗癌剂，其使用受到累积剂量依赖性心脏毒性的限制。表柔比星是阿霉素的衍生物，其治疗指数比利血平更有利，在相同剂量下血液学和心脏毒性较小。本文给出的数据显示了利血平作为化学增敏剂，与表柔比星联合使用时对敏感的P388小鼠白血病细胞（P388/S）和对阿霉素耐药的（P388/DOX）细胞的作用。当单独或联合使用药物时，3H-胸苷掺入DNA的抑制作用被用作药物细胞毒性作用的指标。利血平（1 microM）与表柔比星（1.7、8.6和17.2 microM）联合使用表明，P388/S和P388/DOX细胞系中DNA生物合成抑制作用显著增强。多药耐药细胞最显著的特征是细胞内药物积累减少。与亲代细胞系相比，P388/DOX细胞内表柔比星的积累较少。进一步研究表明，利血平显著增强了两种细胞系中表柔比星的细胞内积累。在P388/DOX细胞系中研究时，利血平和表柔比星联合引起的DNA损伤性质是不可逆的。利血平（5mg/kg）与表柔比星（1mg/kg）联合使用显著增强了表柔比星对荷P388/DOX肿瘤小鼠的抗肿瘤活性。这些研究表明，利血平可用作癌症化疗的佐剂，以增强抗癌药物的抗增殖活性。
