Houghton P J, Cheshire P J, Hallman J D, Lutz L, Friedman H S, Danks M K, Houghton J A
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.
Cancer Chemother Pharmacol. 1995;36(5):393-403. doi: 10.1007/BF00686188.
The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (irinotecan; CPT-11) were evaluated against a panel of 21 human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas, representing an intrinsically chemorefractory malignancy, six lines derived from childhood rhabdomyosarcoma (three embryonal, three alveolar) representing a chemoresponsive histiotype, sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine and melphalan, and three pediatric brain tumors. All tumors were grown at the subcutaneous site. Topotecan was administered by oral gavage 5 days per week for 12 consecutive weeks. The maximum tolerated dose (MTD) was 1.5 mg/kg per dose. Irinotecan was given by i.v. administration daily for 5 days each week for 2 weeks [(d x 5)2](one cycle of therapy), repeated every 21 days. The MTD for three cycles was 10 mg/kg per dose. Treatment was started against advanced tumors. Topotecan caused a high frequency of objective regressions in one of eight colon tumor lines, whereas irinotecan caused complete regressions (CR) of all tumors in three colon lines and a high frequency of CRs in three additional lines. Both drugs demonstrated similar activity against rhabdomyosarcoma xenografts. Topotecan caused CR of all tumors in four of six lines, and irinotecan in five of six lines evaluated. Both agents retained full activity against tumors selected for primary resistance to vincristine, but only irinotecan retained activity against a tumor selected for primary resistance to melphalan. Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing CR in two of three lines and topotecan inducing CR in one of three lines. Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.
对拓扑异构酶I抑制剂9-二甲基-氨基甲基-10-羟基喜树碱（拓扑替康）和7-乙基-10-[4-(1-哌啶基)-1-哌啶基]-羰基氧喜树碱（伊立替康；CPT-11）的长期治疗方案，针对一组源自成人和儿童恶性肿瘤的21种人肿瘤异种移植模型进行了疗效评估。肿瘤包括8种结肠腺癌，代表一种本质上对化疗难治的恶性肿瘤；6种源自儿童横纹肌肉瘤的细胞系（3种胚胎型、3种肺泡型），代表一种对化疗有反应的组织类型；横纹肌肉瘤的亚系，在体内选择对长春新碱和马法兰耐药；以及3种儿童脑肿瘤。所有肿瘤均在皮下部位生长。拓扑替康通过口服灌胃给药，每周5天，连续12周。最大耐受剂量（MTD）为每剂量1.5mg/kg。伊立替康通过静脉给药，每周5天，每天一次，共2周[（d×5）2]（一个治疗周期），每21天重复一次。三个周期的MTD为每剂量10mg/kg。针对晚期肿瘤开始治疗。拓扑替康在8种结肠肿瘤细胞系中的1种中引起高频率的客观缓解，而伊立替康在3种结肠细胞系中使所有肿瘤完全缓解（CR），在另外3种细胞系中引起高频率的CR。两种药物对横纹肌肉瘤异种移植模型显示出相似的活性。拓扑替康在6种细胞系中的4种中使所有肿瘤CR，伊立替康在评估的6种细胞系中的5种中使肿瘤CR。两种药物对选择对长春新碱原发耐药的肿瘤均保持完全活性，但只有伊立替康对选择对马法兰原发耐药的肿瘤保持活性。两种药物对脑肿瘤异种移植模型均显示出良好的活性，伊立替康在3种细胞系中的2种中引起CR，拓扑替康在3种细胞系中的1种中诱导CR。结果表明，这些拓扑异构酶I抑制剂每日低剂量长期给药方案与先前报道的更强烈的短期给药方案相比，疗效相当或更有效。
