Combination of trabectedin and irinotecan is highly effective in a human rhabdomyosarcoma xenograft
Combination of trabectedin and irinotecan is highly effective in a human rhabdomyosarcoma xenograft
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DOI：
10.1097/01.cad.0000172837.67766.6a
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发表时间：
2005-09-01
影响因子：
2.3
通讯作者：
Riccardi, R
中科院分区：
文献类型：
--
作者：
Riccardi, A;Meco, D;Riccardi, R
我们的目的是在体外和体内评估trabectedin （Yondelis, ET-743）和伊立替康（CPT-11）或其主要代谢物SN-38联合使用对人横纹肌肉瘤细胞系的影响。在横纹肌肉瘤细胞系中分析了trabectedin（11小时）后伊立替康或SN-38（24小时）和相反的顺序（伊立替康或SN-38 24小时后trabectedin 1小时）。在体内研究中，trabectedin和伊立替康的剂量分别为0.2和20mg /kg，同时以q4d x 3的时间表给药。体外研究表明，总体加性效应[联合指数（CI）相对接近1.0]，前者方案略优于后者（IC50效应水平：CI = 0.89对1.07）。trabectedin处理对DNA拓扑异构酶I的转录和表达均无影响。在体内，联合用药的治疗结果当然更令人印象深刻：trabectedin和伊立替康联合用药对肿瘤生长产生了强大而持久的影响（肿瘤体积抑制= 89%,log（10）细胞杀伤= 1.6），而每种药物作为单一药物只具有微弱的活性。体外和体内结果之间的差异提示可能涉及宿主细胞的机制，而不是肿瘤细胞。在体内观察到的显著效果可能与直接细胞毒性和抗炎间接作用的结合有关。trabectedin和伊立替康联合在体内非常显著和持久的效果为小儿横纹肌肉瘤患者的临床评估提供了基础。
Our objective was to evaluate in vitro and in vivo the effect of the combination of trabectedin (Yondelis, ET-743) and irinotecan (CPT-11) or its major metabolite SN-38 in a human rhabdomyosarcoma cell line. The schedule trabectedin (11 h) followed by irinotecan or SN-38 (24 h) and the opposite sequence (irinotecan or SN-38 24 h followed by trabectedin 1 h) were analyzed in a rhabdomyosarcoma cell line. In vivo studies were conducted with trabectedin and irinotecan at the doses of 0.2 and 20 mg/kg, respectively, simultaneously administered with a q4d x 3 schedule. In vitro studies indicated an overall additive effect [combination index (CI) relatively close to 1.0], with the former schedule slightly superior to the latter (at the IC50 effect levels: CI = 0.89 versus 1.07). Neither transcription nor expression of DNA topoisomerase I was affected by trabectedin treatment. In vivo the therapeutic results of the combination were certainly more impressive: trabectedin and irinotecan combination caused a strong and long-lasting effect on tumor growth (tumor volume inhibition = 89%, log(10) cell kill = 1.6), whereas each drug given as a single agent was only marginally active. The discrepancy between the in vitro and in vivo results suggests possible mechanisms involving host cells, other than tumor cells. The striking effects of the combination observed in vivo could be related to a combination of a direct cytotoxic and an anti-inflammatory indirect effect. The very marked and long-lasting effect of the trabectedin and irinotecan combination in vivo suggests a basis for a clinical evaluation in pediatric patients with rhabdomyosarcoma.