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Suppression of Cross-Link Formation in Chloroethylnitrosourea-treated DNA by an Activity in Extracts of Human Leukemic Lymphoblasts¹

Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Pulse treatment of DNA with any of several chloroethylnitrosoureas presently in clinical use leads to formation of monoadducts. Further incubation of these monoadducts in the absence of drug leads to DNA interstrand cross-links; however, this cross-link formation is suppressed by a partially purified extract of cultured human leukemic lymphoblasts. The cross-link-suppressing activity copurifies with O⁶-methylguanine-DNA methyltransferase, shows similar kinetics for heat inactivation, and shows similar responses to inhibitors. Reactions for both the cross-link-suppressing and methyltransferase activities reach completion within 5 min at 37°, and both are stoichiometric rather than catalytic. These observations indicate that the number of cross-links induced by the chloroethylnitrosoureas and, hence, their cytotoxicity, should be inversely related to O⁶-methylguanine-DNA methyltransferase content of a cell.

¹ This work was supported by Grants CA 14799 and CA 21765 (NIH) and by the American Labanese Syrian Associated Charities.

² To whom requests for reprints should be addressed.

Received 9/12/83. Accepted 2/ 1/84.

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