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Small intestinal protein metabolism during cancer cachexia and chemotherapy in mice Knowles, Andrew Llewellyn


Cachexia is the leading cause of morbidity and mortality in patients with cancer. Mechanisms The effects of cancer cachexia and chemotherapy on small intestinal protein metabolism and the mechanisms regulating recovery are currently not known. Compromises to small intestinal protein metabolism may impair normal digestive and immune functions within the intestine and may negatively impact the whole body. Colon 26 adenocarcinoma induces cancer cachexia in mice, characteristic to the human condition, and this tumour can be cured with 100% efficacy using the experimental alkylating agent, cystemustine. In the present study, both healthy mice and colon 26 adenocarcinoma bearing mice were given either a single i.p. injection of N-(2- Chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N-nitrosourea (cystemustine)(20 mg/kg) or saline 3 d following the onset of cachexia in colon 26 adenocarcinoma bearing mice. The rate of protein synthesis was determined in vivo using the flooding dose method. The possible involvement of proteolysis was assessed through northern blot hybridization of mRNA encoding components of the major proteolytic systems (lysosomal, calcium dependent, ATP-ubiquitin dependent). Villus and crypt morphology was studied through histological analysis. In tumour bearing mice not treated with chemotherapy, cancer cachexia reduced the rate of protein synthesis in the small intestine relative to healthy mice on a fractional (-15 to -20%, P<O.05) and an absolute basis (-20 to -35%, P<O.05) resulting in a 25% loss of protein mass (P<0.05), and minor alterations to villus and crypt morphology. Northern blot hybridization suggested that protein degradation may not have contributed to wasting as an up-regulation in mRNA levels were not detected (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 damage to intestinal morphology. In contrast, mucosal damage and a 17% reduction in small intestinal protein mass (P<0.05) was evident in healthy mice treated with cystemustine, suggesting that the small intestine in cachectic mice responds differently to chemotherapy than in normal healthy mice. Complete and rapid recovery of small intestinal protein mass in cured mice resulted from an increase in the rate of protein synthesis compared to healthy mice on a fractional (+25%, P<0.05) and absolute basis (+35%, P<0.05); northern blot hybridization suggested no involvement of proteolysis during recovery.

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