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

作者：Chinthalapally V. Rao, Chenyi Wang, Barbara Simi, José G. Rodríguez, Indranie Cooma, Karam El‐Bayoumy, Bandaru S. Reddy · 发表于：PubMed · 年份：2001 · 被引用次数：57 · 研究领域：Inflammatory mediators and NSAID effects、Glutathione Transferases and Polymorphisms、Pharmacogenetics and Drug Metabolism

We have consistently shown that several synthetic Organoselenium compounds are superior cancer chemopreventive agents and less toxic than selenite or certain naturally occurring selenoamino acids. 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) is the lead Organoselenium compound in that it has been shown to be the most effective and the least toxic agent in several experimental cancer models. It is not known whether p-XSC or one of its metabolites is responsible for its chemopreventive efficacy. As an initial step, we synthesized one of its putative metabolites, i.e., the glutathione conjugate 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 azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. p-XSe-SG proved to be very stable over the pH range tested. The maximum tolerated dose 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 period 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 carcinogen 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 c...