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 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.
Samuels
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SE
Food, Nutrition and Health, Faculty of Agricultural Sciences, The University of British Columbia, Vancouver, Canada.
Knowles
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Tilignac
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Debiton
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Madelmont
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JC
Attaix
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D000230:Adenocarcinoma / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D001284:Atrophy; D015152:Blotting, Northern; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D002401:Cathepsin B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D004435:Eating; D015870:Gene Expression; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009607:Nitrosourea Compounds / Q000494:pharmacology / Q000633:toxicity*; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism*; D014452:Ubiquitins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D011506:Proteins; D014452:Ubiquitins; C051263:N'-(2-chloroethyl)-N-(2-(methylsulfonyl)ethyl)-N'-nitrosourea; D002401:Cathepsin B