Rhizoxin is an antineoplastic drug that inhibits tubulin polymerization. In this study, we demonstrated that rhizoxin was approximately twice as active in vitro against a human small-cell lung cancer cell line with non-P-glycoprotein-mediated resistance to vindesine, H69/VDS, as against its parental line, H69. Tubulin polymerization in H69/VDS, demonstrated by Western blot analysis, was inhibited markedly by rhizoxin compared with that in H69, in a concentration-dependent manner. A drug-accumulation study showed that the intracellular rhizoxin level in H69/VDS was 15% lower than that in H69, whereas efflux from H69/VDS was enhanced slightly. These results indicate that enhanced inhibition of tubulin polymerization rather than increased intracellular drug concentration accounted for the higher sensitivity of H69/VDS to rhizoxin. In an experiment using mice with severe combined immunodeficiency and inoculated subcutaneously with H69/VDS, in vivo tumor growth was reduced markedly by three intermittent intraperitoneal doses of rhizoxin compared with that in mice inoculated with H69. Three weeks after the last rhizoxin dose, the relative treated/untreated tumor volumes were 0.29 for H69, but only 0.06 for H69/VDS, indicating that H69/VDS regrowth was minimal even after a 3-week treatment-free period. In conclusion, rhizoxin conquers vindesine resistance of a human small-cell lung cancer cell line in vitro and in vivo.

译文

:Rhizoxin是一种抑制微管蛋白聚合的抗肿瘤药。在这项研究中,我们证明了根霉毒素在体外对人小细胞肺癌细胞株的活性约为非亲本糖蛋白对长春地辛H69 / VDS的抗性(相对于其亲本株H69)的两倍。 Western blot分析表明,与H69相比,根瘤菌素显着抑制了H69 / VDS中的微管蛋白聚合,且呈浓度依赖性。一项药物蓄积研究表明,H69 / VDS中的细胞内根瘤菌素水平比H69低15%,而H69 / VDS的外排量则略有提高。这些结果表明,增强的对微管蛋白聚合的抑制而不是增加的细胞内药物浓度,说明了H69 / VDS对根瘤菌素的敏感性更高。在一项使用严重联合免疫缺陷小鼠并皮下接种H69 / VDS的小鼠进行的实验中,与接种H69的小鼠相比,腹膜内三剂间断性的根瘤菌素显着降低了体内肿瘤的生长。最后一次根瘤菌素给药后三周,H69的相对治疗/未治疗肿瘤体积为0.29,而H69 / VDS仅为0.06,表明即使经过3周的无治疗期,H69 / VDS的再生长也很小。总之,根瘤菌素可在体外和体内克服人类小细胞肺癌细胞株的长春地辛耐药性。

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