Cachectin/tumor necrosis factor: a possible mediator of cancer anorexia in the rat.
Cachectin/tumor necrosis factor (TNF) is a macrophage product which may have a role in cancer cachexia. Recombinant human cachectin/TNF (Cetus Corporation) was administered i.p. twice daily to male F344 rats at varying, nonlethal dosages for either 5 or 10 days, and daily rat food intake and body weight were measured. There was a dose-dependent cachectin/TNF-induced decline in food intake and body weight gain over the treatment period. However, after 1 day rats became tolerant to these effects and increased food intake and gained body weight despite receiving cachectin/TNF. Rats were subsequently inoculated with a transplantable methylcholanthrene-induced sarcoma, and survival was measured. Rats previously treated with high-dose (either 100 or 200 micrograms/kg/day) cachectin/TNF survived significantly longer following tumor inoculation than did control rats given saline or rats given 10 micrograms/kg/day of cachectin/TNF. Analysis of tumor growth curves and tumor weight indicated that high-dose cachectin pretreatment did not retard tumor growth. Analysis of food intake and tumor burden following tumor inoculation indicated that high-dose cachectin pretreatment decreased the reduction in food intake associated with progressive tumor growth and allowed rats to withstand a greater tumor burden at death. Rats immunized with low-dose human cachectin/TNF developed high IgG titers against human TNF, but failed to demonstrate the same protection against a methylcholanthrene-induced tumor challenge as rats made tolerant with repetitive twice daily high-dose cachectin/TNF. The observation of reduced cancer-associated anorexia and increased survival of tumor-bearing rats associated with previous tolerance to exogenous cachectin/TNF strengthens the contention that endogenously produced cachectin may be a factor in the pathogenesis of cancer anorexia in the tumor-bearing rat. The mechanism of this tolerance is unclear but does not appear to be a humoral immune response.
Stovroff
M C
MC
Surgical Metabolism Section, National Cancer Institute, Bethesda, Maryland 20892.
Fraker
D L
DL
Swedenborg
J A
JA
Norton
J A
JA
D000818:Animals; D000855:Anorexia / Q000209:etiology*; D001835:Body Weight / Q000187:drug effects; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D001068:Feeding and Eating Disorders / Q000209:etiology*; D005260:Female; D008297:Male; D009374:Neoplasms, Experimental / Q000503:physiopathology*; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha