Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models.

Published

Journal Article

The activity of temozolomide combined with irinotecan (CPT-11) was evaluated against eight independent xenografts (four neuroblastomas, three rhabdomyosarcomas, and one glioblastoma). In all studies, temozolomide was administered p.o. daily for 5 consecutive days/cycle, found in preliminary studies to be the optimal schedule for administration. Irinotecan was administered i.v. for 5 days for 2 consecutive weeks/cycle. Treatment cycles were repeated every 21 days for a total of three cycles over 8 weeks. In combination, temozolomide and CPT-11 induced complete responses in four neuroblastomas, two rhabdomyosarcomas, and the glioblastoma line. The activity of the combination was significantly greater than the activity of either agent administered alone in four tumor lines. Of interest, the interaction appeared independent of tumor MGMT or mismatch repair phenotype, suggesting that the mechanism of synergy may be independent of O6-methylation by temozolomide. Pharmacokinetic studies indicated no detectable interaction between these two agents. Further, coadministration of CPT-11 appeared to reduce the toxicity of temozolomide in tumor-bearing mice.

Full Text

Duke Authors

Cited Authors

  • Houghton, PJ; Stewart, CF; Cheshire, PJ; Richmond, LB; Kirstein, MN; Poquette, CA; Tan, M; Friedman, HS; Brent, TP

Published Date

  • October 2000

Published In

Volume / Issue

  • 6 / 10

Start / End Page

  • 4110 - 4118

PubMed ID

  • 11051264

Pubmed Central ID

  • 11051264

International Standard Serial Number (ISSN)

  • 1078-0432

Language

  • eng