Berti E, Carrara M, Ragazzi E, D'Ancona S, Berti T
Department of Pharmacology Egidio Meneghetti, University of Padova, 35131 Padova, Italy.
Int J Oncol. 1999 Jul;15(1):155-60.
This study was designed to compare the activity of two MDR modulators, verapamil and dipyridamole, on the in vitro growth of a human colon carcinoma cell line. The aims were: a) to investigate the different sensitivity of the parental cell line (LoVo S) and the doxorubicin-resistant one (LoVo R) towards the treatment with several antiblastics and their associations with verapamil or dipyridamole; b) to evaluate if the combined use of these drugs with verapamil or dipyridamole increases their cytotoxicity; c) to understand whether the mechanism of action of each modulator is the same. Idarubicin and vinblastine were the most active drugs on both cell lines. LoVo R cells showed cross-resistance to vinblastine, teniposide and mitoxantrone, while chemosensitivity towards cisplatin and cyclophosphamide was almost the same in both cell lines. The inhibitory effect on cell growth was enhanced when the drugs were associated with verapamil, but no difference was detected with cisplatin and cyclophosphamide. Verapamil is thus an effective MDR modulator when used with drugs actively pumped out of tumour cells by P-glycoprotein, while it is ineffective with drugs that induce resistance by different mechanisms. When combined with dipyridamole, a significant result was observed in the case of cisplatin, where a marked increase of cytotoxicity was detected.
本研究旨在比较两种多药耐药（MDR）调节剂维拉帕米和双嘧达莫对人结肠癌细胞系体外生长的活性。目的如下：a）研究亲代细胞系（LoVo S）和阿霉素耐药细胞系（LoVo R）对几种抗增殖药物治疗的不同敏感性，以及它们与维拉帕米或双嘧达莫的联合作用；b）评估这些药物与维拉帕米或双嘧达莫联合使用是否会增加其细胞毒性；c）了解每种调节剂的作用机制是否相同。伊达比星和长春碱是对两种细胞系最具活性的药物。LoVo R细胞对长春碱、替尼泊苷和米托蒽醌表现出交叉耐药，而两种细胞系对顺铂和环磷酰胺的化学敏感性几乎相同。当药物与维拉帕米联合使用时，对细胞生长的抑制作用增强，但顺铂和环磷酰胺未检测到差异。因此，维拉帕米与通过P-糖蛋白从肿瘤细胞中主动泵出的药物联合使用时是一种有效的MDR调节剂，而与通过不同机制诱导耐药的药物联合使用时则无效。当与双嘧达莫联合使用时，在顺铂的情况下观察到显著结果，检测到细胞毒性明显增加。
