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JNCI Journal of the National Cancer Institute 1992 84(24):1926-1931; doi:10.1093/jnci/84.24.1926
© 1992 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 84, No. 24, 1926-1931, December 16, 1992
© 1992 Oxford University Press

Enhancement of Nitrosourea Activity in Medulloblastoma and Glioblastoma Multiforme

Henry S. Friedman*,, M. Eileen Dolan, Robert C. Moschel, Anthony E. Pegg, G. Michael Felker, Jeremy Rich, Darell D. Bigner, S. Clifford Schold, Jr.

Departments of Pediatrics and Pathology and the Preuss Laboratory for Brain Tumor Research, Duke University Medical Center Durham, N.C.
Department of Medicine, Duke University Medical Center Durham, N.C.
Department of Pathology, Duke University Medical Center Durham, N.C.
Department of Pathology and the Preuss Laboratory for Brain Tumor Research, Duke University Medical Center Durham, N.C.
Departments of Medicine and Pathology, Duke University Medical Center Durham, N.C.
Division of Hematology-Oncology, The University of Chicago Medical Center Chicago, Ill
Chemistry of Carcinogenesis Laboratory, Advanced Bioscience Laboratories, National Cancer Institute-Frederick Cancer Research and Development Center Frederick, Md
Departments of Cellular and Molecular Physiology and Pharmacology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center Hershey, Pa

Present address: S. C. Schold, Jr., M.D., Department of Neurology, University of Texas, Southwestern Medical Center of Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-9036.

*Correspondence to: Henry S. Friedman, M.D., Duke University Medical Center, Department of Hematology/Oncology, Box 2916, Durham, NC 27710.

Background: Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme, drug resistance occurs frequently, resulting in tumor progression and death. Resistance to nitrosoureas and methylating agents, which damage DNA, can be mediated by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT). Depletion of this protein with alkylguanines or methylating agents, however, restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas (e.g., carmustine [BCNU]). Purpose: This study was designed to determine whether resistance to the activity of nitrosourea (the drug BCNU) in BCNU-resistant human medulloblastoma (D341 Med) and human glioblastoma multiforme (D-456 MG) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine. Methods: Xenografts were grown subcutaneously in athymic BALB/c mice. BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2, 75 mg/m2, or 38 mg/m2—i.e., 1.0, 0.75, or 0.38, respectively, of the dose lethal to 10% of treated animals (LD10). Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine (240 mg/m2) or with streptozocin (600 mg/m2) daily for 4 days. Response was assessed by tumor growth delay and tumor regression. AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment, at the time tumors were excised. Results: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4%, 25%, and 95% of control values, respectively, in D341 Med and 0%, 0%, and 25% of control values, respectively, in D-456 MG 1 hour after injection. After 6 hours, levels changed to 7%, 61%, and 116% of control values in D341 Med and 0%, 79%, and 21% of control values in D-456 MG, respectively. Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10. Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft In contrast, treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone, reflecting the more efficient depletion of AGAT by O6-benzylguanine. Following therapy with BCNU plus O6-benzylguanine at 038 LD10, tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts. Conclusion: We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU, which would allow subsequent design of phase I clinical trials. [J Natl Cancer Inst 84:1926–1931, 1992]


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