O-6-Benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma

Local delivery of carmustine (BCNU) via biodegradable polymers pro-longs su rvival against experimental brain tumors and in human clinical trials. O-6- Benzylguanine (O-6-BG), a potent inhibitor of the DNA repair protein, O-6-a lkylguanine-DNA alkyltransferase (AGT), has been shown to reduce nitrosoure a resistance and, thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models, In this report, we demonstrate that O-6-BG can pot entiate the activity of BCNU delivered intracranially via polymers in rats challenged with a lethal brain tumor. Fischer 344 rats received a lethal in tracranial challenge of 100,000 F98 glioma cells (F98 cells have significan t AGT activity, 328 fmol/mg protein). Five days later, animals receiving an i,p, injection of O-6-BG (50 mg/kg) 2 h prior to BCNU polymer (3.8% BCNU b y weight) implantation had significantly improved survival (n = 7; median s urvival, 34 days) over animals receiving either O-6-BG alone (n = 7; median survival, 22 days; P = 0.0002) or BCNU polymer alone (n = 8; median surviv al, 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 ev idence of treatment-related toxicity. These findings suggest that O-6-BG ca n potentiate the effects of interstitially delivered BCNU and, for tumors e xpressing significant AGT, may be necessary for the BCNU to provide a meani ngful therapeutic benefit. Given the clinical use of BCNU polymers against malignant gliomas, concurrent treatment with O-6-BG may provide an importan t addition to our therapeutic armamentarium.