Protein metabolism in the small intestine during cancer cachexia and chemotherapy in mice

The impact of cancer cachexia and chemotherapy on small intestinal protein metabolism and its subsequent recovery was investigated. Cancer cachexia wa s induced in mice with colon 26 adenocarcinoma, which is a small and slow-g rowing tumor characteristic of the human condition, and can be cured with 1 00% efficacy using an experimental nitrosourea, cystemustine (C6H12ClN3O4S) . Both healthy mice and tumor-bearing mice were given a single i.p. injecti on of cystemustine (20 mg/kg) 3 days after the onset of cachexia, Cancer ca chexia led to a reduced its vivo rate of protein synthesis in the small int estine 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 dept h (P < 0.05), In treated mice, acute cytotoxicity of chemotherapy did not p romote 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 i n healthy mice treated with cystemustine, suggesting that the effects of ch emotherapy on the small intestine in a state of cancer cachexia are not add itive, which was an unexpected finding. Complete and rapid recovery of smal l intestinal protein mass in cured mice resulted from an increase in the ra te of protein synthesis compared with healthy mice (23-34%; P < 0.05), Nort hern hybridizations of mRNA encoding components of the major proteolytic sy stems suggested that proteolysis may not have mediated intestinal wasting o r recovery, A major clinical goal should be to design methods to improve sm all intestinal protein metabolism before the initiation of chemotherapy.