Reddy B S, Rivenson A, El-Bayoumy K, Upadhyaya P, Pittman B, Rao C V
Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, NY 10595, USA.
J Natl Cancer Inst. 1997 Apr 2;89(7):506-12. doi: 10.1093/jnci/89.7.506.
Observational and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. However, many forms of selenium are toxic. Consequently, the development of efficacious compounds with low toxicity has been pursued.
Two synthetic organoselenium compounds, p-methoxy-benzyl selenocyanate (p-methoxy-BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC), were tested for their ability to inhibit colon carcinogenesis in rats that were treated with the carcinogen azoxymethane and fed low- or high-fat diets.
Groups of 5-week-old male F344 rats (42 animals/ group) were fed either a high-fat diet or a low-fat diet with or without added p-methoxy-BSC (10 or 20 parts per million [ppm]) or p-XSC (20 ppm). Two weeks later, 30 animals in each group received a subcutaneous injection of azoxymethane (15 mg/kg body weight); 1 week later, they received a second injection. The remaining 12 rats in each group received two injections of saline. Three days after the second injection of carcinogen or saline, animals being fed diets with p-methoxy-BSC or p-XSC were switched to corresponding organoselenium-free low- or high-fat diets for the remainder of the study to determine the effects of the selenium compounds on the initiation phase of colon carcinogenesis. At that time, groups of animals that had been maintained on organoselenium-free low- or high-fat diets were switched to diets containing p-methoxy-BSC or p-XSC until the end of the study to determine the effects of these compounds on the postinitiation phase of colon carcinogenesis. All animals were killed during the 38th week after azoxymethane or saline treatment, and histopathologic analysis of the colon tumors was performed. Colon tumor incidence and multiplicity were analyzed statistically.
No obvious toxic effects were observed following dietary administration of 10 or 20 ppmp-methoxy-BSC or 20 ppm p-XSC. Administration of 20 ppm p-methoxy-BSC in a high-fat diet during the initiation and postinitiation phases of colon carcinogenesis significantly (statistically) reduced colon tumor incidence; 10 ppmp-methoxy-BSC in a high-fat diet significantly reduced colon tumor incidence but only when it was given during the postinitiation phase. Colon tumor incidence was also significantly reduced when 20 ppm p-XSC was given in a high-fat diet during the initiation phase of colon carcinogenesis. When 20 ppm p-XSC was administered in either a high-fat diet or a low-fat diet during the postinitiation phase, both colon tumor incidence and multiplicity were significantly reduced; the greatest reductions were in animals fed a low-fat diet.
In this model system, p-methoxy-BSC and p-XSC are effective agents for the chemoprevention of colon cancer. The effects of p-XSC were enhanced in animals fed a low-fat diet.
观察性和实验性研究表明，膳食补充硒可抑制结肠癌的发展。然而，许多形式的硒具有毒性。因此，人们一直在寻求开发低毒的有效化合物。
测试两种合成有机硒化合物，对甲氧基苄基硒氰酸盐（p-甲氧基-BSC）和1,4-亚苯基双（亚甲基）硒氰酸盐（p-XSC）在接受致癌物偶氮甲烷处理并喂食低脂或高脂饮食的大鼠中抑制结肠癌发生的能力。
将5周龄雄性F344大鼠（每组42只动物）分为四组，分别喂食高脂饮食或低脂饮食，其中两组分别添加10或20 ppm的p-甲氧基-BSC，另外两组分别添加20 ppm的p-XSC。两周后，每组30只动物皮下注射偶氮甲烷（15 mg/kg体重）；1周后，再注射一次。每组其余12只大鼠注射两次生理盐水。在第二次注射致癌物或生理盐水三天后，喂食含p-甲氧基-BSC或p-XSC饮食的动物在研究剩余时间内改为相应的无有机硒低脂或高脂饮食，以确定硒化合物对结肠癌发生起始阶段的影响。此时，一直喂食无有机硒低脂或高脂饮食的动物组改为含p-甲氧基-BSC或p-XSC的饮食直至研究结束，以确定这些化合物对结肠癌发生起始后阶段的影响。在偶氮甲烷或生理盐水处理后的第38周处死所有动物，并对结肠肿瘤进行组织病理学分析。对结肠肿瘤的发生率和多发性进行统计学分析。
喂食10或20 ppm p-甲氧基-BSC或20 ppm p-XSC后未观察到明显的毒性作用。在结肠癌发生的起始阶段和起始后阶段，高脂饮食中添加20 ppm p-甲氧基-BSC可显著降低结肠肿瘤发生率；高脂饮食中添加10 ppm p-甲氧基-BSC可显著降低结肠肿瘤发生率，但仅在起始后阶段给予时有效。在结肠癌发生的起始阶段，高脂饮食中添加20 ppm p-XSC也可显著降低结肠肿瘤发生率。在起始后阶段，高脂饮食或低脂饮食中添加20 ppm p-XSC，结肠肿瘤的发生率和多发性均显著降低；在低脂饮食喂养的动物中降低最为明显。
在该模型系统中，p-甲氧基-BSC和p-XSC是预防结肠癌的有效药物。在低脂饮食喂养的动物中，p-XSC的效果增强。
