Structure-activity relationships among the ortho-, meta- and para-isomers of phenylenebis (methylene)seleno cyanate (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 high-fat diet (23.5% corn oil). Rats were fed for 1 week prior to oral administration of a single dose of [H-3]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 DMBA-DNA binding in the mammary tissues. The inhibition at 5, respectively 15 ppm Se in the form of XSC isomers and at 30 mu M, respectively 90 mu M 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 latter appears to be slightly more effective than its sulfur analog p-XTC. 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.