Chemoprevention of colon cancer by a glutathione conjugate of 1,4-phenylenebis(methylene)selenocyanate, a novel organoselenium compound with low toxicity

We have consistently shown that several synthetic Organoselenium compounds are superior canter chemopreventive agents and less toxic than selenite or certain naturally occurring selenoamino acids, 1,4-Phenylenebis(methylene)s elenocyanate (p-XSC) is the lead Organoselenium compound in that it has bee n shown to be the most effective and the least toxic agent in several exper imental cancer models, It is not known whether p-XSC or one of its metaboli tes is responsible for its chemopreventive efficacy, As an initial step, we synthesized one of its putative metabolites, i.e., the glutathione conjuga te of p-XSC (p-XSe-SG), and determined its stability In the pH range from 2 to 8 and in the diet under normal feeding conditions. We also assessed its maximum tolerated dose and examined its chemopreventive efficacy against a zoxymethane (AOM)Induced colon carcinogenesis in male F344 rats, p-XSe-SG p roved to be very stable over the pH range tested, The maximum tolerated dos e of p-XSe-SG determined in a 6-week subchronic toxicity study was found to be >210 ppm (>40 ppm selenium) when the compound was added to AIN-76A high -fat diet, To assess the efficacy of this agent in the postinitiation perio d of colon carcinogenesis, male F344 rats 6 weeks of age were fed the high- fat diet, and at beginning of weeks 7 and 8, all of the rats intended for c arcinogen treatment were given AOM at a dose of 15 mg/kg body weight by s.c , injection. Two days after the carcinogen treatment, the groups of rats co nsuming the high-fat control diet began their respective high-fat experimen tal diet regimens with 0, 56, or 84 ppm p-XSe-SG (0.1, 10, and 15 ppm of se lenium) supplementation, All animals continued on their respective diets fu r 38 weeks after the AOM-treatment and were then killed. Colon tumors were evaluated histologically using routine procedures and were also analyzed Fo r cyclooxygenase (COX)-1 and COX-2 expression and enzymatic activities, The results indicate that p-XSeSG administered during the post-initiation stag e significantly inhibited both the incidence (P < 0.05-0.01) and the multip licity (P < 0.05-0.005) of AOM-induced colon adenocarcinomas. This agent al so greatly suppressed the multiplicity (P < 0.01-0.001) of AOM-induced exop hytic adenocarcinomas in a dose-dependent manner. Feeding of 56 or 84 ppm p -XSe-SG in the diet significantly suppressed total COX activity (P < 0.02 t o -0.01) and COX-2 specific activity (P < 0.005-0.0005) but had minimal eff ect on the protein expression levels of COX-1 and COX-2, These results sugg est that the neu ly developed synthetic Organoselenium compound, p-XSe-SG, is stable in the diet and at wide pH ranges, inhibits colon carcinogenesis when administered during the postinitiation stage, and inhibits COX activit y, Compared with previous efficacy studies and considering the toxicity ass ociated with selenium, p-XSe-SG seems to be the least toxic Organoselenium chemopreventive agent thus far tested in the experimental colon carcinogene sis, Studies are in progress to delineate whether p-XSe-SG is also effectiv e when administered during the progression stage of colon carcinogenesis.