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DNA Damage and Cytotoxicity of 2-Chloroethyl (Methylsulfonyl)methanesulfonate (NSC 338947) Produced in Human Colon Carcinoma Cells with or without Methylating Agent Pretreatment

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

2-Chloroethyl (methylsulfonyl)methanesulfonate (ClEtSoSo) was more toxic to the BE (Mer^-) cell line than to the HT-29 (Mer⁺) colon carcinoma. The sensitivity of the BE cells closely paralleled the induction of DNA interstrand cross-links by ClEtSoSo. No DNA interstrand cross-link formation was detected in the HT-29 cells after exposure to ClEtSoSo. Pretreatment of the HT-29 cells with methylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine or streptozotocin increases their sensitivity to ClEtSoSo. Little or no increase in the toxicity of ClEtSoSo was found in BE cells after methylating agent pretreatment. Despite the increase in cell killing, no DNA interstrand cross-links were induced by ClEtSoSo after N-methyl-N'-nitro-N-nitrosoguanidine pretreatment. In contrast, streptozotocin pretreatment allowed ClEtSoSo to form DNA interstrand cross-links in HT-29 cells. The production of DNA strand breaks by ClEtSoSo was observed in HT-29 cells both with and without methylating agent pretreatment. These results suggest that the mechanism of ClEtSoSo may differ from other chloroethylating agents such as the chloroethylnitrosoureas. In addition, there may be a difference in the mechanism by which streptozotocin or N-methyl-N'-nitro-N-nitrosoguanidine pretreatment causes an increased cell killing in a previously resistant human colon carcinoma cell line.

¹ Present address: Department of Pharmacology, Fox Chase Cancer Center, Central and Shelmire Avenues, Philadelphia, PA 19111. To whom requests for reprints should be addressed.

Received 2/10/86. Revised 4/ 7/86. Accepted 4/28/86.