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An Apparent Inactivation of Initiated Cells by the Potent Inhibitor of Two-Stage Mouse Skin Tumorigenesis, Bis(2-chloroethyl)sulfide¹

McArdle Laboratory for Cancer Research, Medical Center, University of Wisconsin, Madison, Wisconsin 53706

Sulfur mustard, a potent inhibitor of two-stage skin tumorigenesis, appears to act primarily by inactivating initiated cells rather than by suppressing the biochemical response to the promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Thus, when the increase of epidermal-dermal p-tosyl-L-arginine methyl ester esterase activity in TPA-treated mice was compared with the response of mice similarly treated but receiving a pretreatment with sulfur mustard, no statistical difference was found. In both cases activity was increased to 4 to 5 times the level found in acetone-treated controls. Moreover, pretreatment with sulfur mustard failed to influence the ability of the promoter to inhibit an isoproterenol-induced accumulation of cyclic adenosine 3':5'-phosphate. Finally, sulfur mustard applied 24 hr after the first three applications of TPA did not inhibit the 300-fold increase in ornithine decarboxylase activity observed after the fourth application of the promoter.

In tumor induction experiments four applications of sulfur mustard given 24 hr after the first four applications of the promoter resulted in a 60% reduction in tumors/mouse. A similar reduction was observed when four applications of sulfur mustard were given during the interval between initiation with 7,12-dimethylbenz[a]anthracene and the beginning of promotion. If sulfur mustard inhibits tumorigenesis by a general cytotoxicity, an effect on the biochemical responsiveness of the skin to TPA should be observed. As stated above no such effect was observed. Furthermore, previous investigators have reported that sulfur mustard did not inhibit either the hyperplasia or the inflammation associated with preneoplasia of the skin. These facts combined with the tumor inhibition data strongly indicate that sulfur mustard in some way selectively inactivates initiated cells.

¹ This work was supported by Grants CA-07175 and T32-CA 09020 from the National Cancer Institute, NIH.

Received 7/21/77. Accepted 9/20/77.