Inaba M, Nagashima K
Jpn J Cancer Res. 1986 Feb;77(2):197-204.
Twelve monomeric or dimeric alkaloids from Vinca rosea Linn., which had been reported to have little or no antitumor activity, were investigated to determine their combined effects with either vincristine or daunorubicin on in vitro cell growth of a P388 subline resistant to vincristine and cross-resistant to anthracyclines. We found that the combinations at subcytotoxic concentrations induced significant growth inhibition of the resistant cells, but not of the sensitive cells. Of the alkaloids examined, catharine, vindoline, catharanthine, vincarodine, and lochnerine were able to bring about complete inhibition of cell growth. Further in vitro study using vindoline revealed that at 10 micrograms/ml it was able to completely reverse not only resistance to vincristine but also cross-resistance to vinblastine, daunorubicin, and adriamycin. In addition, we found that vinca alkaloids active in reversing resistance possess potent activities to enhance the net uptake of not only vincristine but also daunorubicin by the resistant cells, and this effect was proved to result from their inhibitory action on the active efflux process. These results provide further support for our hypothesis that both anthracyclines and vinca alkaloids can inhibit their own efflux process by interacting with the cell membrane, and this similarity provides a basis for their reciprocal cross-resistance, irrespective of their different chemical structures.
对长春花中12种单体或二聚体生物碱进行了研究，这些生物碱据报道几乎没有或没有抗肿瘤活性，研究其与长春新碱或柔红霉素联合对长春新碱耐药且对蒽环类药物交叉耐药的P388亚系体外细胞生长的影响。我们发现，亚细胞毒性浓度的联合用药对耐药细胞有显著的生长抑制作用，但对敏感细胞没有。在所检测的生物碱中，长春花宁、长春多灵、长春质碱、长春罗定碱和洛柯宁碱能够完全抑制细胞生长。进一步使用长春多灵进行的体外研究表明，在10微克/毫升时，它不仅能够完全逆转对长春新碱的耐药性，还能逆转对长春碱、柔红霉素和阿霉素的交叉耐药性。此外，我们发现具有逆转耐药活性的长春花生物碱不仅对耐药细胞增强长春新碱的净摄取有强大作用，对柔红霉素也有此作用，并且这种作用被证明是由于它们对主动外排过程的抑制作用。这些结果为我们的假说提供了进一步支持，即蒽环类药物和长春花生物碱都可以通过与细胞膜相互作用来抑制它们自身的外排过程，这种相似性为它们的相互交叉耐药性提供了基础，而不管它们不同的化学结构如何。
