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Effect of O⁶-Methylguanine on DNA Interstrand Cross-Link Formation by Chloroethylnitrosoureas and 2-Chloroethyl(methylsulfonyl)methanesulfonate¹

Department of Physiology and Cancer Research Center, The Milton S. Hershey Medical Center, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033 [M. E. D., A. E. P.], and Laboratory of Cell Biology and Pharmacology, Section of Hematology-Oncology, Department of Medicine, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153 [N. K. H., L. C. E.]

Exposure of HT29 cells in culture to O⁶-methylguanine is known to result in a reduction in O⁶-alkylguanine-DNA alkyltransferase (AGT) activity and an enhancement of sensitivity to the cytotoxic effects of chloroethylating agents. Since cytotoxicity of these agents may be mediated by the formation of interstrand cross-links, alkaline elution analysis was performed on HT29 cells treated with 1-(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and Clomesone [2-chloroethyl(methylsulfonyl)methanesulfonate] in the presence or absence of O⁶-methylguanine pretreatment to determine if the enhanced toxicity was due to an increase in the number of cross-links formed. Interstrand cross-linking by 1-(2-chloroethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was increased by pretreatment with 0.4 mM O⁶-methylguanine for 24 h. Cross-linking by Clomesone was observed only in cells exposed to 0.4 mM O⁶-methylguanine for 24 h prior to administration of the drug and for 12 h after administration, suggesting that the resynthesis of the AGT may prevent the cross-linking by Clomesone. Complete recovery of AGT activity after reduction to 20 to 30% of the basal level upon treatment with 0.4 mM O⁶-methylguanine required between 8 h and 15 h in both HT29 cells and in Raji cells which were also sensitized to 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea by exposure to O⁶-methylguanine. These data suggest that the enhancement of chloroethylnitrosourea toxicity after treatment with O⁶-methylguanine may be related to an increase in the number of DNA cross-links and that the relatively rapid rate of AGT recovery plays a role in prevention of cross-links resulting from Clomesone.

¹ This research was supported by NIH Grants CA18137 (A. E. P.) and CA 45628 (L. C. E.).

² To whom requests for reprints should be addressed.

Received 12/ 7/87. Revised 3/28/88. Accepted 4/ 4/88.

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