Antitumor activity of temozolomide combined with irinotecan is partly independent of O-6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models

The activity of temozolomide combined with irinotecan (CPT-11) was evaluate d against eight independent xenografts (four neuroblastomas, three rhabdomy osarcomas, and one glioblastoma), In all studies, temozolomide was administ ered 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 repeat ed 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 Iine. The activity of the combi nation was significantly greater than the activity of either agent administ ered alone in four tumor lines, Of interest, the interaction appeared indep endent of tumor MGMT or mismatch repair phenotype, suggesting that the mech anism of synergy may be independent of O-6-methylation by temozolomide, Pha rmacokinetic 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.