Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft

Vikas J. Patel, Gertrude B. Elion, Peter J. Houghton, Stephen Keir, Anthony E. Pegg, Stewart P. Johnson, M. Eileen Dolan, Darell D. Bigner, Henry S. Friedman

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Temozolomide, an imidazole tetrazinone, and CPT-11, a camptothecin derivative, have previously been shown to have anti-central nervous system tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of temozolomide plus CPT-11 displays a schedule-dependent enhancement of antitumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.

Original languageEnglish (US)
Pages (from-to)4154-4157
Number of pages4
JournalClinical Cancer Research
Volume6
Issue number10
StatePublished - 2000
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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