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.]
Abstract
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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported in part by USPHS Awards CA23099, CA71628, CA14799, and CA21765 (Cancer Center Support Grant) from the National Cancer Institute and by American, Lebanese, Syrian Associated Charities.
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↵2 To whom requests for reprints should be addressed, at Molecular Pharmacology, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794. Phone: (901) 495-3440; Fax: (901) 521-1668; E-mail: peter.houghton{at}stjude.org
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↵3 The abbreviations used are: MGMT, O6-methylguanine-DNA methyltransferase; MMR, mismatch repair; CPT-11, irinotecan[ 7-ethyl-10-(4-[1-piperidino)-1-piperidino]-carbonyloxy-camptothecin]; SN-38, 7-ethyl-10-hydroxy-camptothecin; CR, complete response; MTIC, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; AUC, area under the concentration-time curve.
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- Accepted July 14, 1900.
- Received May 23, 1900.
- Revision received July 14, 1900.
