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Basic Sciences

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

Elisabeth Uy Dexter, Toyoko S. Yamashita, Cheryl Donovan and Stanton L. Gerson
Elisabeth Uy Dexter
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Toyoko S. Yamashita
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Cheryl Donovan
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Stanton L. Gerson
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DOI:  Published July 1989
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Abstract

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.

Footnotes

  • ↵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 December 19, 1988.
  • Revision received March 30, 1989.
  • Accepted April 6, 1989.
  • ©1989 American Association for Cancer Research.
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July 1989
Volume 49, Issue 13
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Modulation of O6-Alkylguanine-DNA Alkyltransferase in Rats following Intravenous Administration of O6-Methylguanine
Elisabeth Uy Dexter, Toyoko S. Yamashita, Cheryl Donovan and Stanton L. Gerson
Cancer Res July 1 1989 (49) (13) 3520-3524;

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Modulation of O6-Alkylguanine-DNA Alkyltransferase in Rats following Intravenous Administration of O6-Methylguanine
Elisabeth Uy Dexter, Toyoko S. Yamashita, Cheryl Donovan and Stanton L. Gerson
Cancer Res July 1 1989 (49) (13) 3520-3524;
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