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Modulation of O⁶-Alkylguanine-DNA Alkyltransferase in Rats following Intravenous Administration of O⁶-Methylguanine¹

Departments of Medicine [E. D., C. D., S. G.], Pediatrics [T. Y.], and Epidemiology, and Biostatistics [T. Y.], and the R. L. Ireland Cancer Center [E. D., T. Y., C. D., S. G.], University Hospitals of Cleveland and the Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106

The purine analogue O⁶-methylguanine is an effective biochemical modulator of the DNA repair protein O⁶-alkylguanine-DNA alkyltransferase. Inactivation of the alkyltransferase by O⁶-methylguanine sensitizes tumor cells to nitrosoureas in vitro. The pharmacokinetics of O⁶-methylguanine were evaluated in female Sprague-Dawley rats following administration of a single 40 mg/kg i.v. bolus dose. Two-compartment pharmacokinetic analysis revealed a terminal elimination half-life of 2.3 ± 0.68 h, a total body clearance of 6.0 ± 0.53 ml/min/kg, and a volume of distribution at steady state of 948 ± 186 ml/kg. To inactivate the alkyltransferase, 80 mg/kg O⁶-methylguanine was given at 0 and 2 h. Alkyltransferase decreased in bone marrow, kidney, lung, spleen, and intestine by 20–90%. Regeneration of alkyltransferase activity was observed 22–70 h after the first bolus dose of O⁶-methylguanine. A continuous infusion protocol, which achieved a steady state serum concentration of 10.3 ± 1.5 µg O⁶-methylguanine/ml at 15 h, resulted in a similar degree of inactivation of tissue alkyltransferase to that observed following bolus drug infusion. O⁶-Methylguanine tissue concentrations, including that determined in brain, were 1.7- to 4-fold higher than that in serum, indicating that O⁶-methylguanine is concentrated in most if not all tissues. These studies establish pharmacokinetic parameters of O⁶-methylguanine in rats and suggest that effective biochemical modulation of alkyltransferase can be achieved in vivo. Further studies are indicated to assess the extent to which biochemical modulation of alkyltransferase reduces tumor nitrosourea resistance in vivo.

¹ Supported in part by Public Health Service Grants ESCA00134, from the National Institute of Environmental Health Sciences, and CA45609 and P30CA43703, from the National Cancer Institute.

² Recipient of a Silber Student Award from the American Cancer Society, Ohio Division, Cuyahoga County Unit.

³ Recipient of an Edward Mallinckrodt Jr. Foundation Scholar Award. To whom requests for reprints should be addressed, at University Hospitals of Cleveland, 2074 Abington Rd., Cleveland, OH 44106.

Received 12/19/88. Revised 3/30/89. Accepted 4/ 6/89.