Eradication of Human Medulloblastoma Tumor Xenografts with a Combination of O6-Benzyl-2′-deoxyguanosine and 1,3-Bis(2-chloroethyl)-1-nitrosourea1
- Department of Neurosurgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8855 [D. M. K.]; National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201 [R. C. M.]; Departments of Cellular and Molecular Physiology and Pharmacology, Pennsylvania State University, College of Medicine, The Milton Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]; and Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710 [S. C. S.]
Abstract
O6-Benzyl-2′-deoxyguanosine (dBG), a water-soluble inhibitor of O6-methylguanine-DNA methyltransferase (MGMT), potentiates the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against MGMT-positive, BCNU-resistant Daoy human medulloblastoma tumor xenografts in athymic mice (S. C. Schold et al., Cancer Res., 56: 2076–2081, 1996). Such potentiation was comparable to that observed for O6-benzylguanine, the prototype MGMT inhibitor that is currently undergoing clinical trials. In this study, we optimized the therapeutic effect of the dBG and BCNU combination against brain tumor xenografts without inducing substantial toxicity in the host by adjusting the doses of both compounds. dBG was escalated from 133 mg/m2 to 200 and 300 mg/m2, whereas corresponding doses of BCNU were reduced from 25 mg/m2 to 17 and 11 mg/m2, respectively. The growth delays of 30.2, 38.4, and 22.3 days, respectively, observed for the above regimens suggest that the optimal drug combination is not achieved with maximum doses of dBG. In fact, the highest doses of dBG (300 mg/m2) contributed to more frequent BCNU-related toxicities, despite the reduced BCNU dosage, and a reduction of the therapeutic effect. Toxicity was related to the depletion of MGMT activity in the gut of host mice and was manifested by edema, inflammation, and hemorrhage in the bowel wall by subsequent BCNU administration. With additional dosage adjustments, we found that tumor suppression of >90 days without toxicity was observed at 200 mg/m2 dBG and 23 mg/m2 BCNU. At these doses, tumors were eradicated (regressed to an undetectable size for >90 days) in 8 of 12 animals. Thus, dBG is the first of the MGMT inhibitors to show a curative effect in combination with BCNU against a human central nervous system tumor xenograft in athymic 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 by National Cancer Institute Grants CA 57725 and CA78561 and the National Cancer Institute, Department of Health and Human Services, under contract with ABL.
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↵2 To whom requests for reprints should be addressed, at Department of Neurosurgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8855. Phone: (214) 648-6314; Fax: (214) 648-2265.
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↵3 The abbreviations used are: MGMT, O6-methylguanine-DNA methyltransferase; dBG, O6-benzyl-2′-deoxyguanosine; BG, O6-benzylguanine; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; CNS, central nervous system; PEG, polyethylene glycol.
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↵4 Unpublished observations.
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- Accepted August 16, 1999.
- Received May 6, 1999.
- Revision received August 12, 1999.
