Thompson J, Zamboni W C, Cheshire P J, Lutz L, Luo X, Li Y, Houghton J A, Stewart C F, Houghton P J
Departments of Hematology Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Clin Cancer Res. 1997 Mar;3(3):423-31.
The efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11) has been examined against a panel of six independently derived neuroblastoma xenografts. Intensive courses of therapy, where irinotecan was administered i.v. daily 5 days per week for two consecutive weeks [(dx5)2; defined as 1 cycle], were compared to more protracted low-dose schedules where cycles were repeated every 21 days for a total of three courses ¿abbreviated [(dx5)2]3¿. When administered (dx5)2 for a single cycle, the maximum tolerated daily dose was 40 mg/kg. Irinotecan induced a high frequency of complete regressions (CRs) in four of the six lines examined; however, most tumors achieving CR regrew during the period of observation (12 weeks). Furthermore, there was no advantage in high-dose regimens as compared to low dose (10 mg/kg) on the same schedule. Protracted schedules of administration, where three courses of therapy were given at 21-day intervals ¿[(dx5)2]3¿ i.v. were examined at 10 and 5 mg/kg/dose. Even at the lower dose level, irinotecan caused 100% CR in all tumor lines that were maintained at 12 weeks. To determine the minimum dose levels required to induce objective regressions of neuroblastoma xenografts, decreasing doses were examined using the [(dx5)2]3 i.v. schedule. At 2.5 mg/kg/dose, >90% of NB-1643, NB-1691, NB-1382.2, and NB-EB xenografts demonstrated CR, whereas at 1.25 mg/kg/dose, all six tumor lines evaluated demonstrated objective regressions (>/=50% volume reduction), with a high frequency of CRs in four tumor lines. The 10-hydroxy-7-ethyl CPT lactone single-day systemic exposure measured with the minimum dose (2.5 mg/kg) associated with complete response was 198, 257, and 228 ng.h/ml for mice bearing NB-1643, NB-1691, and NB-EB tumors, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by parenteral administration, and that efficacy is schedule dependent.
已经针对一组六种独立衍生的神经母细胞瘤异种移植瘤研究了拓扑异构酶I抑制剂7-乙基-10-(4-[1-哌啶基]-1-哌啶基)-羰基氧基-喜树碱（伊立替康，CPT-11）的疗效。将强化治疗疗程（伊立替康每周5天静脉注射，连续两周[(dx5)2；定义为1个周期]）与更延长的低剂量方案进行比较，后者每21天重复一个周期，共三个疗程（缩写为[(dx5)2]3）。当以[(dx5)2]进行单个周期给药时，最大耐受日剂量为40mg/kg。伊立替康在所检测的六个细胞系中的四个中诱导了高频率的完全缓解（CR）；然而，大多数达到CR的肿瘤在观察期（12周）内复发。此外，与相同方案的低剂量（10mg/kg）相比，高剂量方案没有优势。研究了延长给药方案，即每21天间隔静脉注射三个疗程[(dx5)2]3，剂量分别为10mg/kg和5mg/kg。即使在较低剂量水平，伊立替康在所有维持12周的肿瘤细胞系中都引起了100%的CR。为了确定诱导神经母细胞瘤异种移植瘤客观缓解所需的最低剂量水平，使用[(dx5)2]3静脉注射方案研究了递减剂量。在2.5mg/kg/剂量时，>90%的NB-1643、NB-1691、NB-1382.2和NB-EB异种移植瘤显示出CR，而在1.25mg/kg/剂量时，所有评估的六个肿瘤细胞系都显示出客观缓解（体积缩小>/=50%），四个肿瘤细胞系中CR频率很高。与完全缓解相关的最低剂量（2.5mg/kg）测量的10-羟基-7-乙基CPT内酯单日全身暴露量，对于携带NB-1643肿瘤、NB-1691肿瘤和NB-EB肿瘤的小鼠分别为198、257和228ng.h/ml。这些结果表明，儿童神经母细胞瘤异种移植瘤对胃肠外给药的伊立替康高度敏感，且疗效取决于给药方案。
