E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonami de), an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of 26 human tumor cell lines (IC50 = 0.06-0.8 microg/ml), in contrast to vincristine (VCR; IC50 = 0.0002-0.04 microg/ml), 5-fluorouracil (IC50 = 0.2-30 microg/ml), Adriamycin (IC50 = 0.002-0.7 microg/ml), mitomycin C (IC50 = 0.007-3 microg/ml), 1-beta-D-arabinofuranoxylcytosine (IC50 = 0.005 to >30 microg/ml), camptothecin (IC50 = 0.002-0.4 microg/ml), and cisplatin (IC50 = 0.5-20 microg/ml). It caused a dose-dependent increase in the percentage of mitotic cells in parallel with a decrease in cell proliferation, like VCR. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth-inhibitory activity. 14C-labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR. E7010 was active against two kinds of VCR-resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, four E7010-resistant P388 cell lines showed no cross-resistance to VCR, a different pattern of resistance to podophyllotoxin, and collateral sensitivity to Taxol. Therefore, E7010 is a novel tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol.

译文

E7010 (N-[2-[(4-羟基苯基) 氨基]-3-吡啶基]-4-甲氧基苯磺酰胺),一种口服活性磺酰胺抗肿瘤剂,目前处于I期临床试验中,与长春新碱 (VCR; IC50 = 0.0002-0.04微克/毫升),5-氟尿嘧啶 (IC50 = 0.2-30微克/毫升) 相比,对一组26种人类肿瘤细胞系 (IC50 = 0.06-0.8微克/毫升) 表现出相当一致的生长抑制活性,阿霉素 (IC50 = 0.002-0.7微克/毫升),丝裂霉素c (IC50 = 0.007-3微克/毫升),1-β-d-阿拉伯呋喃氧基胞嘧啶 (IC50 = 0.005至> 30微克/毫升),喜树碱 (IC50 = 0.002-0.4微克/毫升),和顺铂 (IC50 = 0.5-20微克/毫升)。它引起有丝分裂细胞百分比的剂量依赖性增加,同时细胞增殖下降,如VCR。它还显示了微管蛋白聚合的剂量依赖性抑制,它与细胞生长抑制活性密切相关。14c标记的E7010与纯化的微管蛋白结合,这种结合被秋水仙碱抑制,而不受VCR抑制。然而,它的结合特性不同于秋水仙碱。与VCR一样。E7010对两种抗VCR的P388细胞系具有活性,其中一种由于P-糖蛋白的过表达而表现出多药耐药性 (对紫杉醇耐药),而另一种则没有表现出多药耐药性 (对紫杉醇敏感)。此外,四种E7010-resistant的P388细胞系对VCR没有交叉抗性,对鬼臼毒素的抗性不同模式以及对紫杉醇的附带敏感性。因此,e7010是一种新型的微管蛋白结合剂,具有比VCR更宽的抗肿瘤谱,并且具有与VCR或紫杉醇不同的特性。

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