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Clinical Cancer Research Vol. 6, 4110-4118, October 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Antitumor Activity of Temozolomide Combined with Irinotecan Is Partly Independent of O6-Methylguanine-DNA Methyltransferase and Mismatch Repair Phenotypes in Xenograft Models1

Peter J. Houghton2, Clinton F. Stewart, Pamela J. Cheshire, Lois B. Richmond, Mark N. Kirstein, Catherine A. Poquette, Ming Tan, Henry S. Friedman and Thomas P. Brent

Departments of Molecular Pharmacology [P. J. H., T. P. B.], Pharmaceutical Science [C. F. S., P. J. C., L. B. R., M. N. K.], and Biostatistics and Epidemiology [C. A. P., M. T.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, and Duke University Medical Center, Durham, North Carolina 27710 [H. S. F.]

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.




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