Human tumor necrosis factor α (TNF) inhibits tumor growth, but its effects on tumor and skeletal muscle protein metabolism in vivo have not been adequately studied. Walker 256 carcinosarcoma growth rate was followed over an 11-day period in Sprague-Dawley rats. Tumor-bearing rats received either saline or 50 µg of TNF (Genentech, Inc.) s.c. on day 8 of tumor growth. This single dose of TNF reduced tumor protein growth during a 2-day posttreatment period from 27.6 ± 4.4 to 10.5 ± 3.7%/day (mean ± SE; P < 0.01). The rate of in vivo incorporation of l-[1-14C]leucine into skeletal muscle protein was significantly increased (P < 0.05) from 5.1 ± 0.2%/day in the saline-treated tumor-bearing rats to 7.7 ± 1.3%/day in the TNF-treated tumor-bearing rats. The latter value was not statistically different from the 9.2 ± 0.9%/day observed in the tumor-free control animals. TNF administration significantly increased both the total and individual acid-soluble skeletal muscle amino acid concentrations in tumor-bearing rats by an average of 86 ± 7%, compared to values in saline-treated tumor-bearing rats. Similarly, acid-soluble skeletal muscle 3-methyl-histidine concentrations increased from 66 ± 14 to 113 ± 19 pmol/g protein (P < 0.05). Tumor protein synthesis in the TNF-treated group was 50% greater than in the saline-treated group, whether expressed as %/day (72.7 ± 9.1 versus 47.9 ± 4.8; P < 0.05) or was µg/g tumor/min (58.7 ± 7.7 versus 40.7 ± 4.5; P < 0.05). In contrast, estimated tumor protein degradation rates were increased by over 200% in the TNF-treated rats, compared to the values in the saline-treated rats [62.1 ± 10.7 versus 20.3 ± 6.0%/day (P < 0.01) and 50.0 ± 8.9 versus 17.5 ± 5.4 µg/g tumor/min (P < 0.01)]. Thus, TNF appears to stimulate tumor protein degradation more than protein synthesis, explaining the overall decrease in tumor growth.
Supported in part by NIH Grant T32-DK07461, Clinical Nutrition Research Unit Young Investigator Award 5P01-CA42710, and Harbor-UCLA Medical Center, Research and Education Institute, Investigator Research Award.