Samuels S E, Knowles A L, Tilignac T, Debiton E, Madelmont J C, Attaix D
Food, Nutrition and Health, Faculty of Agricultural Sciences, The University of British Columbia, Vancouver, Canada.
Cancer Res. 2000 Sep 1;60(17):4968-74.
The impact of cancer cachexia and chemotherapy on small intestinal protein metabolism and its subsequent recovery was investigated. Cancer cachexia was induced in mice with colon 26 adenocarcinoma, which is a small and slow-growing tumor characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12ClN3O4S). Both healthy mice and tumor-bearing mice were given a single i.p. injection of cystemustine (20 mg/kg) 3 days after the onset of cachexia. Cancer cachexia led to a reduced in vivo rate of protein synthesis in the small intestine relative to healthy mice (-13 to -34%; P < 0.05), resulting in a 25% loss of protein mass (P < 0.05), and decreased villus width and crypt depth (P < 0.05). In treated mice, acute cytotoxicity of chemotherapy did not promote further wasting of small intestinal protein mass, nor did it result in further damage to intestinal morphology. In contrast, mucosal damage and a 17% reduction in small intestinal protein mass (P < 0.05) were evident in healthy mice treated with cystemustine, suggesting that the effects of chemotherapy on the small intestine in a state of cancer cachexia are not additive, which was an unexpected finding. Complete and rapid recovery of small intestinal protein mass in cured mice resulted from an increase in the rate of protein synthesis compared with healthy mice (23-34%; P < 0.05). Northern hybridizations of mRNA encoding components of the major proteolytic systems suggested that proteolysis may not have mediated intestinal wasting or recovery. A major clinical goal should be to design methods to improve small intestinal protein metabolism before the initiation of chemotherapy.
研究了癌症恶病质和化疗对小肠蛋白质代谢及其后续恢复的影响。在患有结肠26腺癌的小鼠中诱发癌症恶病质，该肿瘤体积小、生长缓慢，具有人类疾病的特征，并且使用实验性亚硝基脲西司莫司汀（C6H12ClN3O4S）可100%有效治愈。在恶病质发作3天后，对健康小鼠和荷瘤小鼠均进行单次腹腔注射西司莫司汀（20mg/kg）。与健康小鼠相比，癌症恶病质导致小肠蛋白质合成的体内速率降低（-13%至-34%；P<0.05），导致蛋白质质量损失25%（P<0.05），绒毛宽度和隐窝深度减小（P<0.05）。在接受治疗的小鼠中，化疗的急性细胞毒性既没有促进小肠蛋白质质量的进一步消耗，也没有导致肠道形态的进一步损伤。相比之下，用西司莫司汀治疗的健康小鼠出现黏膜损伤，小肠蛋白质质量降低17%（P<0.05），这表明化疗对处于癌症恶病质状态的小肠的影响不是累加的，这是一个意外发现。治愈小鼠小肠蛋白质质量的完全快速恢复是由于蛋白质合成速率相对于健康小鼠增加（23%至34%；P<0.05）。对编码主要蛋白水解系统成分的mRNA进行的Northern杂交表明，蛋白水解可能并未介导肠道消瘦或恢复。一个主要的临床目标应该是在开始化疗之前设计改善小肠蛋白质代谢的方法。
