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Topoisomerase I interactive drugs in children with cancer

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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 of 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 pharmacokinetics and pharmacodynamics of the CMT analogs studied in children are summarized, and future studies of these agents are discussed.

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Authors and Affiliations

  1. Department of Hematolgy-Oncology, St. Jude Children's Research Hospital, USA

    Amar Gajjar, Richard L. Heideman, Wayne L. Furman, William H. Meyer & Charles B. Pratt

  2. Department of Pediatrics, College of Medicine University of Tennessee, Memphis, USA

    Amar Gajjar, Richard L. Heideman, Wayne L. Furman, William H. Meyer & Charles B. Pratt

  3. Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN, USA

    Peter J. Houghton

  4. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, 38105, Memphis, TN, USA

    Clinton F. Stewart, William C. Zamboni & William R. Crom

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  1. Clinton F. Stewart
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Address for offprints: Clinton F. Stewart, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA

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Stewart, C.F., Zamboni, W.C., Crom, W.R. et al. Topoisomerase I interactive drugs in children with cancer. Invest New Drugs 14, 37–47 (1996). https://doi.org/10.1007/BF00173681

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