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

Clin Cancer Res. 2000 Oct;6(10):4154-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Camptothecin / administration & dosage*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use*
  • Dacarbazine / administration & dosage*
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use*
  • Female
  • Humans
  • Irinotecan
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Nervous System Neoplasms / drug therapy*
  • Temozolomide
  • Time Factors
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Alkylating
  • Antineoplastic Agents, Phytogenic
  • Irinotecan
  • Dacarbazine
  • Camptothecin
  • Temozolomide