Riccardi Anna, Meco Daniela, Ubezio Paolo, Mazzarella Giorgio, Marabese Mirko, Faircloth Glynn T, Jimeno José, D'Incalci Maurizio, Riccardi Riccardo
Department of Pediatric Oncology, Catholic University, Rome, Italy.
Anticancer Drugs. 2005 Sep;16(8):811-5. doi: 10.1097/01.cad.0000172837.67766.6a.
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 (1 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%, log10 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.
我们的目标是在体外和体内评估曲贝替定（Yondelis，ET - 743）与伊立替康（CPT - 11）或其主要代谢产物SN - 38联合用药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曲贝替定（1小时）后接伊立替康或SN - 38（24小时）的给药方案以及相反顺序（伊立替康或SN - 38 24小时后接曲贝替定1小时）。体内研究中，曲贝替定和伊立替康分别以0.2和20 mg/kg的剂量，按照每4天一次、共给药3次的方案同时给药。体外研究表明总体上具有相加作用[联合指数（CI）相对接近1.0]，前一种给药方案略优于后一种（在IC50效应水平：CI = 0.89对1.07）。曲贝替定处理未影响DNA拓扑异构酶I的转录或表达。在体内，联合用药的治疗效果确实更令人印象深刻：曲贝替定和伊立替康联合用药对肿瘤生长产生了强烈且持久的影响（肿瘤体积抑制率 = 89%，对数10细胞杀伤率 = 1.6），而每种药物单独使用时活性仅很微弱。体外和体内结果的差异表明可能存在涉及宿主细胞而非肿瘤细胞的机制。体内观察到的联合用药的显著效果可能与直接细胞毒性和抗炎间接效应的组合有关。曲贝替定和伊立替康联合用药在体内非常显著且持久的效果为对小儿横纹肌肉瘤患者进行临床评估提供了依据。
