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O⁶-Benzylguanine Potentiates the Antitumor Effect of Locally Delivered Carmustine against an Intracranial Rat Glioma¹

Department of Neurological Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland 21205 [L. D. R., P. S., B. M. T., H. B., J. W.], and Section of Hematology-Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637 [M. E. D.]

Local delivery of carmustine (BCNU) via biodegradable polymers prolongs survival against experimental brain tumors and in human clinical trials. O⁶-Benzylguanine (O⁶-BG), a potent inhibitor of the DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase (AGT), has been shown to reduce nitrosourea resistance and, thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models. In this report, we demonstrate that O⁶-BG can potentiate the activity of BCNU delivered intracranially via polymers in rats challenged with a lethal brain tumor. Fischer 344 rats received a lethal intracranial challenge of 100,000 F98 glioma cells (F98 cells have significant AGT activity, 328 fmol/mg protein). Five days later, animals receiving an i.p. injection of O⁶-BG (50 mg/kg) 2 h prior to BCNU polymer (3.8% BCNU by weight) implantation had significantly improved survival (n = 7; median survival, 34 days) over animals receiving either O⁶-BG alone (n = 7; median survival, 22 days; P = 0.0002) or BCNU polymer alone (n = 8; median survival, 25 days; P = 0.0001). Median survival for the control group (n = 8) was 23.5 days. Moreover, there was no physical, behavioral, or pathological evidence of treatment-related toxicity. These findings suggest that O⁶-BG can potentiate the effects of interstitially delivered BCNU and, for tumors expressing significant AGT, may be necessary for the BCNU to provide a meaningful therapeutic benefit. Given the clinical use of BCNU polymers against malignant gliomas, concurrent treatment with O⁶-BG may provide an important addition to our therapeutic armamentarium.

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