Schedule-dependent Activity of Temozolomide plus CPT-11 against a Human Central Nervous System Tumor-derived Xenograft

Schedule-dependent Activity of Temozolomide plus CPT-11 against a Human Central Nervous System Tumor-derived Xenograft1

Departments of Surgery [V. J. P., S. K., S. P. J., H. S. F.], Pathology [D. D. B., H. S. F.], and Pharmacology [G. B. E.], Duke University Medical Center, Durham, North Carolina 27710; Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [P. J. H.]; Department of Medicine, University of Chicago, Chicago, Illinois 60637 [M. E. D.]; and Department of Cellular and Molecular Physiology, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]

Abstract

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.

Footnotes

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↵1 Supported by NIH Grants 2RO1 NS30245 and 5P50NS20023 and the PhRMA Foundation.
↵2 Dr. Gertrude B. Elion died on February 21, 1999 during the completion of this work.
↵3 To whom requests for reprints should be addressed, at Department of Surgery, Box 3624, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-5301; Fax: (919) 681-1697.
↵4 The abbreviations used are: AGT, O⁶-alkylguanine-DNA alkyltransferase; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea.
↵5 P. J. Houghton, C. F. Stewart, M. N. Kirstein, C. A. Poquette, M. Tan, H. S. Friedman, and T. P. Brent. Antitumor activity of temozolomide combined with irinotecan is partly independent of MGMT and mismatch repair phenotypes in xenograft models, submitted for publication.
- Accepted July 17, 1900.
- Received May 23, 1900.
- Revision received July 17, 1900.