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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Patel, VJ; Elion, GB; Houghton, PJ; Keir, S; Pegg, AE; Johnson, SP; Dolan, ME; Bigner, DD; Friedman, HS

Published Date

  • October 2000

Published In

Volume / Issue

  • 6 / 10

Start / End Page

  • 4154 - 4157

PubMed ID

  • 11051270

International Standard Serial Number (ISSN)

  • 1078-0432

Language

  • eng

Conference Location

  • United States