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

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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 - Jan 1 2000

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Patel, V. J., Elion, G. B., Houghton, P. J., Keir, S., Pegg, A. E., Johnson, S. P., Dolan, M. E., Bigner, D. D., & Friedman, H. S. (2000). Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft. Clinical Cancer Research, 6(10), 4154-4157.