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Protection Against the Acute and Delayed Toxicity of Mustards and Mustard-Like Compounds

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Annual rept. 1 Sep 1985-28 Feb 87, Final rept. 1 Sep 1982-28 Feb 1987

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Many of the toxicities of the sulfur mustards are caused by damage which these agents inflict on cellular DNA. This study was undertaken because previous data on DNA modifications caused by these agents did not seem adequate to explain all of their biological effects. We have shown that a model sulfur mustards, chloroethyl ethyl sulfide CEES, modifies the 6 position of guanine in DNA, producing O6-ethylthioethyl deoxyguanosine. Although this lesion amounts to only 0.1 of the total DNA alkylation, its presence helps to explain the mutagenic effects of this agent. We have confirmed that the 7 position of guanine and the 3 position of adenine are the major sites of DNA modification approximately 16 of the products of reaction between DNA and CEES have not been identified. Literature data indicate that other repair factors would be effective in repairing this DNA modification. Furthermore, we have obtained preliminary evidence that 7-ethylthioethyl deoxyguanosine is repaired by a factor in rat liver. Thus, it appears that mammalian cells have some ability to repair the DNA modifications caused by sulfur mustards. This suggests that resistance to the toxic effects of these agents can be enhanced. An incidental finding in these studies is that CEES polymerizes. This reaction completely inactivates a single armed mustard and would partially inactivate a bifunctional mustard. Keywords Mustards Sulfur mustards Chloroethyl ethyl Sulfide Hemisulfur mustard Carcinogenesis Mutagenesis.

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  • Chemical, Biological and Radiological Warfare

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