Ciomei Marina, Croci Valter, Ciavolella Antonella, Ballinari Dario, Pesenti Enrico
Department of Biology, Drug Discovery Oncology, Nerviano Medical Sciences, Nerviano, Milan, Italy.
Clin Cancer Res. 2006 May 1;12(9):2856-61. doi: 10.1158/1078-0432.CCR-05-1859.
The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drug-treated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.
新型吲哚咔唑类药物依多卡琳（J-107088，原称ED-749）在药代动力学和药效动力学方面均与其他拓扑异构酶I抑制剂不同。在体外实验中，它比喜树碱类药物更具活性，并且在31种不同的人类癌细胞系中具有可变的细胞毒性活性。当与体外测试的其他针对各种癌细胞系的药物联合使用时，依多卡琳对细胞增殖也具有大于相加的抑制作用。进行本体内研究是为了扩展体外研究结果，以表征依多卡琳单独使用或与其他药物（即5-氟尿嘧啶、伊立替康、顺铂、奥沙利铂和SU11248）联合使用时在HCT-116人结肠癌异种移植模型中的抗肿瘤作用。治疗效果基于药物治疗组与载体对照组相比肿瘤指数增长起始的延迟情况。在所有研究中，依多卡琳作为单一药物以及与其他药物联合使用时均具有活性。联合治疗产生了大于相加的效果，其程度取决于具体的给药方案。这些实验中的毒性极小。在所有359只接受治疗的小鼠中，死于毒性的6只小鼠来自高剂量依多卡琳/奥沙利铂组。结果表明，依多卡琳作为单一药物、与标准方案以及其他拓扑异构酶抑制剂联合使用或与新型药物（如多靶点酪氨酸激酶抑制剂SU11248）联合使用时，可能是结肠癌的有效化疗药物。
