Preclinical pharmacology of the antitumor agent O-6-methylguanine in CDF1 mice
Cancer Chemotherapy and Pharmacology, ISSN: 0344-5704, Vol: 33, Issue: 3, Page: 197-202
1993
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Article Description
O-6-methylguanine (O6-mG), a guanine analog recently shown to be a potent inhibitor of alkylguanine-DNA alkyltransferase, has been found to potentiate the antitumor activity of nitrosoureas, in particular, carmustine (BCNU), in resistant cell lines (HT-29 mer+) and is targeted for development as a modulating agent with chloroethyl nitrosoureas. A high-performance liquid chromatography (HPLC) assay of O6-mG in plasma has been developed using a μC18 reverse-phase column. O6-mG and the internal standard deoxyguanosine (dGuo) were eluted with a linear gradient of from 15% to 35% methanol in 0.5 M ammonium acetate (pH 6.5) at a flow rate of 1 ml/min. The assay was linear over a 4-log concentration range with a detection limit of 0.1 μg/ml. The within-run and between-run coefficients of variation (CV) were found to be 8.1% and 9.3%, respectively. The pharmacokinetics (PK) of O6-mG were investigated in healthy CDF1 mice following separate i.v. and i.p. administrations. At 20 mg/kg i.v., plasma O6-mG gave a biexponential profile with a terminal half-life (t) of 24 min and a total clearance (CLT) of 23.7 ml min kg. Higher doses (40-80 mg/kg) revealed a fluctuating third phase, probably due to enterohepatic cycling. Dose-dependent kinetics as measured by CLT and area under the plasma-concentration curve (AUC) values were also seen. Following i.p. dosing, O6-mG was completely absorbed and available to the circulation. No acute toxicity was observed in the animals, except for mild sedation, a possible side effect of the 10% ethanol used in the formulation. Studies on the cellular metabolism of highly purified [H]-O6-mG have shown that the compound is not anabolized by a human lymphoblastoid cell line (CEM). Biochemistry studies have shown that the parent molecule is inactivating the alkylguanine-DNA alkyltransferase (AGT), thus exerting its pharmacological effect. © 1993 Springer-Verlag.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0027369520&origin=inward; http://dx.doi.org/10.1007/bf00686216; http://www.ncbi.nlm.nih.gov/pubmed/8269600; http://link.springer.com/10.1007/BF00686216; http://www.springerlink.com/index/10.1007/BF00686216; http://www.springerlink.com/index/pdf/10.1007/BF00686216; https://dx.doi.org/10.1007/bf00686216; https://link.springer.com/article/10.1007/BF00686216
Springer Science and Business Media LLC
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