Stewart C F, Zamboni W C, Crom W R, Gajjar A, Heideman R L, Furman W L, Meyer W H, Houghton P J, Pratt C B
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Invest New Drugs. 1996;14(1):37-47. doi: 10.1007/BF00173681.
Topotecan, irinotecan, and 9-aminocamptothecin (9-AC) are analogs of the plant alkaloid 20(S)-camptothecin (CMT), the prototypical DNA topoisomerase I interactive agent. These agents interact with the topoisomerase I-DNA complex and prevent resealing topoisomerase I-mediated DNA single-strand breaks. This eventual leads to double-strand DNA breaks and apoptosis or cell death. Topotecan, irinotecan, and 9-AC have shown significant activity in mice bearing pediatric solid tumor xenografts; the greatest antitumor responses were found with protracted continuous schedules. Preclinical data also suggest that maintenance of an exposure-duration threshold (EDT) may be required to achieve optimal cytotoxicity. Pediatric Phase I trials have evaluated the toxicity and safety to camptothecin analogs in children with relapsed solid tumors and relapsed acute leukemia. The primary dose-limiting toxicity (DLT) for the CMT analogs in children has been myelosuppression, except for mucositis observed with the 120-hr continuous topotecan infusion schedule. Pharmacodynamic relationships with these analogs have been reported between systemic exposure, and myelosuppression and mucositis. Although not a primary objective of the early Phase I studies, antitumor responses have been reported. In this review, the pharmacokinetic and pharmacodynamics of the CMT analogs studied in children are summarized, and future studies of these agents are discussed.
拓扑替康、伊立替康和9-氨基喜树碱（9-AC）是植物生物碱20(S)-喜树碱（CMT）的类似物，CMT是典型的DNA拓扑异构酶I相互作用剂。这些药物与拓扑异构酶I-DNA复合物相互作用，阻止拓扑异构酶I介导的DNA单链断裂重新封闭。这最终导致双链DNA断裂以及细胞凋亡或死亡。拓扑替康、伊立替康和9-AC在携带小儿实体瘤异种移植物的小鼠中显示出显著活性；在持续较长时间的连续给药方案中观察到最大的抗肿瘤反应。临床前数据还表明，可能需要维持暴露持续时间阈值（EDT）以实现最佳细胞毒性。小儿I期试验评估了喜树碱类似物对复发实体瘤和复发急性白血病患儿的毒性和安全性。CMT类似物在儿童中的主要剂量限制性毒性（DLT）一直是骨髓抑制，但120小时持续输注拓扑替康方案观察到有黏膜炎。已报道了这些类似物的全身暴露与骨髓抑制和黏膜炎之间的药效学关系。尽管早期I期研究的主要目的不是评估抗肿瘤反应，但已有相关报道。在本综述中，总结了在儿童中研究的CMT类似物的药代动力学和药效学，并讨论了这些药物未来的研究。
