Topoisomerase I interactive drugs in children with cancer

Clinton F. Stewart, William C. Zamboni, William R. Crom, Amar Gajjar, Richard L. Heideman, Wayne L. Furman, William H. Meyer, Peter J Houghton, Charles B. Pratt

Research output: Contribution to journalReview article

39 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)37-47
Number of pages11
JournalInvestigational New Drugs
Volume14
Issue number1
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

Fingerprint

Camptothecin
Type I DNA Topoisomerase
irinotecan
9-aminocamptothecin
Topotecan
Mucositis
Pharmaceutical Preparations
Neoplasms
Appointments and Schedules
Pediatrics
Single-Stranded DNA Breaks
Double-Stranded DNA Breaks
Alkaloids
Heterografts
Leukemia
Cell Death
Pharmacokinetics
Maintenance
Apoptosis
Safety

Keywords

  • Camptothecin
  • DNA topoisomerase
  • Irinotecan
  • Pediatric oncology
  • Topotecan

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Stewart, C. F., Zamboni, W. C., Crom, W. R., Gajjar, A., Heideman, R. L., Furman, W. L., ... Pratt, C. B. (1996). Topoisomerase I interactive drugs in children with cancer. Investigational New Drugs, 14(1), 37-47. https://doi.org/10.1007/BF00173681

Topoisomerase I interactive drugs in children with cancer. / Stewart, Clinton F.; Zamboni, William C.; Crom, William R.; Gajjar, Amar; Heideman, Richard L.; Furman, Wayne L.; Meyer, William H.; Houghton, Peter J; Pratt, Charles B.

In: Investigational New Drugs, Vol. 14, No. 1, 01.01.1996, p. 37-47.

Research output: Contribution to journalReview article

Stewart, CF, Zamboni, WC, Crom, WR, Gajjar, A, Heideman, RL, Furman, WL, Meyer, WH, Houghton, PJ & Pratt, CB 1996, 'Topoisomerase I interactive drugs in children with cancer', Investigational New Drugs, vol. 14, no. 1, pp. 37-47. https://doi.org/10.1007/BF00173681
Stewart CF, Zamboni WC, Crom WR, Gajjar A, Heideman RL, Furman WL et al. Topoisomerase I interactive drugs in children with cancer. Investigational New Drugs. 1996 Jan 1;14(1):37-47. https://doi.org/10.1007/BF00173681
Stewart, Clinton F. ; Zamboni, William C. ; Crom, William R. ; Gajjar, Amar ; Heideman, Richard L. ; Furman, Wayne L. ; Meyer, William H. ; Houghton, Peter J ; Pratt, Charles B. / Topoisomerase I interactive drugs in children with cancer. In: Investigational New Drugs. 1996 ; Vol. 14, No. 1. pp. 37-47.
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