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[Cancer Research 55, 2853-2857, July 1, 1995]
© 1995 American Association for Cancer Research
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Activity of Temozolomide in the Treatment of Central Nervous System Tumor Xenografts1

Henry S. Friedman2, M. Eileen Dolan, Anthony E. Pegg, Susan Marcelli, Stephen Keir, Joseph J. Catino, Darell D. Bigner and S. Clifford Schold, Jr.

Departments of Pediatrics [H. S. F., S. K., S. M.] and Pathology [H. S. F., D. D. B.] and the Preuss Laboratory for Brain Tumor Research [H. S. F., D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; Section of Hematology-Oncology, Department of Medicine, The University of Chicago Medical Center, Chicago, Illinois 60637 [M. E. D.]; Departments of Cellular and Molecular Physiology and Pharmacology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]; Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235 [S. C. S.]; and the Schering-Plough Research Institute, Kenilworth, New Jersey 07033 [J. J. C.]

The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 1,3-bis(2-chloroethyl)-1-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8–7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from -3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea.

1 This study was supported by NIH Grants NS20023, CA11898, CA56115, NS30245, CA57725, and NS20581 and by American Cancer Society Grant DHP-67 E.

2 To whom requests for reprints should be addressed, at Duke University Medical Center, Department of Pathology, Box 3156, Durham, NC 27710.

Received 3/13/95. Accepted 5/ 1/95.




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