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Formation of DNA Interstrand Cross-Links by the Novel Chloroethylating Agent 2-Chloroethyl(methylsulfonyl)methanesulfonate: Suppression by O⁶-Alkylguanine-DNA Alkyltransferase Purified from Human Leukemic Lymphoblasts¹

Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101

The formation of DNA interstrand cross-links was compared in DNA treated with either 1,3-bis(2-chloroethyl)-1-nitrosourea or 2-chloroethyl-(methylsulfonyl)methanesulfonate. DNA that was pulse treated briefly with either of these drugs continued to form cross-links at 37°C for over 8 h after drug removal, indicating that such DNA contained stable precursors of cross-links. When human O⁶-alkylguanine-DNA alkyltransferase was added to the drug-treated DNA further cross-link formation was prevented at all points during this protracted time course, indicating that these stable cross-link precursors also remained substrates for this repair enzyme. Although the pattern of 2-chloroethyl(methylsulfonyl)methanesulfonate-induced cross-link formation and susceptibility to suppression by O⁶-alkylguanine-DNA alkyltransferase resembled that for 1,3-bis(2-chloroethyl)-1-nitrosourea, quantitative differences in the rates of cross-link formation and in the amounts of O⁶-alkyguanine-DNA alkyltransferase required to suppress cross-link formation suggest that critical differences exist between these agents.

¹ The research was supported by Grants CA14799, CA36888, CA21765, and CA23944 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed at the Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38101.

Received 11/14/86. Revised 3/23/87. Accepted 3/30/87.

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