Structure-activity relationships among the ortho-, meta- and para- isomers of phenylenebis(methylene)selenocyanate (XSC) as inhibitors of 7,12- dimethylbenz(a)anthracene-DNA binding in mammary glands of female CD rats

As shown earlier p-XSC inhibits DMBA-induced mammary cancer in female CD rats. This inhibition is due, in part, to inhibition of DMBA-DNA adduct formation in the target organ. We have now utilized the DMBA-DNA binding assay to evaluate the chemopreventive potential of positional isomers of XSC (o-, m- and p-XSC) applied at selenium doses of 5 and 15 ppm; p-XTC, the sulfur analog of p-XSC, was used at an equimolar dose to determine whether selenium is required for the observed inhibitory effect. Selenium and sulfur compounds were administered in a semipurified highfat diet (23.5% corn oil). Rats were fed for I week prior to oral administration of a single dose of [³H]DMBA (5 mg/rat); animals were sacrificed 24 h later, DNA was isolated from mammary fat pads and levels of total binding were determined. All agents produced a dose-dependent inhibition of DMBADNA binding in the mammary tissues. The inhibition at 5, respectively 15 ppm Se in the form of XSC isomers and at 30 μM, respectively 90 μM in the form of p-XTC was: o-XSC (27%, 42%); m-XSC (32%, 47%); p-XSC (22%, 29%); and p-XTC (10%, 20%); only inhibition by dietary o-XSC and m-XSC at 15 ppm Se reached statistical significance (p<0.05). Thus, o-XSC and m-XSC equally inhibit DMBA-DNA binding and both are better inhibitors than p-XSC; the latterappears to be slightly more effective than its sulfur analog pXTC. Clearly, the structure of the selenium-containing compound is a critical factor in determining the extent of inhibition of DMBA-DNA binding. The described short-term in vivo assay may constitute the basis for future selection of chemopreventive agents in the rat mammary tumor model system.