摘要

This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non-homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects. 

译文

本研究 :( i) 研究了 lurbinectedin (PM01183) 和 zalpsis 的体外细胞毒性和作用模式®(PM00104) 与特定修复机制缺陷的细胞系中的 trabectedin 进行比较，(ii) 评估了它们对一系列小鼠肿瘤和人类异种移植物的体内抗肿瘤活性。这三种化合物在肿瘤细胞系上诱导的抗增殖活性、 DNA 损伤和细胞周期扰动非常相似。核苷酸切除修复 (NER) 缺陷细胞对 trabectedin 、 lurbinectedin 和 zalpsis 的耐药性大约增加了四倍®。缺乏非同源末端连接 (NHEJ) 、 MRN 复合物和跨病变合成 (TLS) 的细胞对这三种化合物稍微更敏感 (大约五倍) 而同源重组 (HR) 缺陷的细胞明显更敏感 (150-200 倍)。这三个化合物在几个体内模型中都显示了良好的抗肿瘤活性。Lurbinectedin 和 trabetedin 在小鼠肿瘤和异种移植瘤中具有相似的抗肿瘤活性模式，而 zalpis®似乎有明显的活动范围。事实上，在体外细胞毒效力和体内抗肿瘤活性之间没有发现任何关系, 表明除了直接的细胞毒性机制，其他宿主介导的作用也参与体内药理作用。