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Release of 7-Alkylguanines from N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea-modified DNA by 3-Methyladenine DNA Glycosylase II¹

Department of Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 [Y. H., C. A. C., D. B. L.] and Molecular Spectroscopy Section [M. C. K.], Southern Research Institute, Birmingham, Alabama 35255-5305

Purified bacterial 3-methyladenine DNA glycosylase II releases four 7-alkylguanines from [³H]N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea-modified DNA: 7-(2-hydroxyethyl)guanine, 1,2-bis(7-guanyl)ethane, 7-(2-chloroethyl)guanine, and 7-(2-ethoxyethyl)guanine. 7-(2-Ethoxyethyl)guanine, a new compound, is formed as a result of an interaction with ethanol, a common solvent for the 2-haloethylnitrosoureas. Of the four 7-alkylguanines which are released from [³H]N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea-modified DNA, 7-(2-hydroxyethyl)guanine is released at a rate very much slower than the other three. As shown by a study of the spontaneous decomposition of the corresponding 7-alkyldeoxyguanines, differences in chemical stability do not appear to explain the slow release of 7-(2-hydroxyethyl)guanine.

In view of previous results showing a difference in the distribution of alkylation products between sensitive and resistant glial cell lines, the broad specificity of this enzyme suggests that glycosylase activity could play a role in cellular resistance to 2-haloethylnitrosoureas.

¹ Supported by Grants CA-44499 and CA-47103 from the National Cancer Institute. Presented in part at the 80th Annual Meeting of the American Association for Cancer Research, May 1989, San Francisco, CA (11).

² Present address: Institut Gustave-Roussy, Groupe Radiochimie de l'ADN, Rue Camille Desmoulins, 94805 Villejuif Cedex, France.

³ Present address: Wellcome Research Laboratories, 3030 Cornwallis Road, Research Triangle Park, NC 27709.

⁴ To whom reprint requests should be addressed, at Department of Pharmacology, University of Massachusetts, Medical Center, 55 Lake Avenue North, Worcester, MA 01655.

Received 6/16/90. Accepted 10/26/90.

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