title: Topoisomerase I interactive drugs in children with cancer.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
authors.forename: W C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: W R
authors.initials: WR
authors.lastname: Crom
authors.forename: A
authors.initials: A
authors.lastname: Gajjar
authors.forename: R L
authors.initials: RL
authors.lastname: Heideman
authors.forename: W L
authors.initials: WL
authors.lastname: Furman
authors.forename: W H
authors.initials: WH
authors.lastname: Meyer
authors.forename: P J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: C B
authors.initials: CB
authors.lastname: Pratt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002648:Child; D004249:DNA Damage / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019772:Topotecan
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin