O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma
| Autor: | L D, Rhines, P, Sampath, M E, Dolan, B M, Tyler, H, Brem, J, Weingart |
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| Rok vydání: | 2000 |
| Předmět: |
Drug Implants
Male Guanine Brain Neoplasms Drug Synergism Glioma Gliosarcoma Carmustine Xenograft Model Antitumor Assays Rats Inbred F344 Rats Stereotaxic Techniques O(6)-Methylguanine-DNA Methyltransferase Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured Animals Humans Enzyme Inhibitors Antineoplastic Agents Alkylating Medulloblastoma |
| Zdroj: | Cancer research. 60(22) |
| ISSN: | 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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