Abstract
The effect of the synthetic progesterone, megestrol acetate, on weight loss induced by both tumour necrosis factor alpha (TNF) as a model for the cachexia accompanying the acquired immunodeficiency syndrome and by a cachexia-inducing tumour (MAC16) has been studied in NMRI mice. Megestrol acetate was effective in preventing weight loss in both model systems with treated animals having an increase in intake of both food and water. Megestrol acetate was unable to prevent loss of body weight in animals pair-fed with TNF treated animals, suggesting that the increase in food and water intake was responsible for the increase in body weight. Analysis of body composition showed that the major contribution to the increase in body weight in animals treated with megestrol acetate was an increase in water content, although there was also an increase in carcass fat in animals bearing the MAC16 tumour given the high dose of megestrol acetate. Animals bearing the MAC16 tumour had a significant increase in tumour weight after treatment with megestrol acetate, possibly owing to the increased plasma glucose levels. These results suggest that an increase in appetite and weight gain alone are not sufficient to justify the anticachectic effect of a particular agent and that body composition analysis and tumour growth rate are very important parameters.
Highlights
We have previously carried out a dose-response relationship of tumour necrosis factor a (TNF)-induced weight loss in female NMRI mice and found optimal weight loss with no toxicity produced by a dose of 7.5 x 107 U kg-' (Mahony et al, 1988; Mahony & Tisdale, 1988)
When administered intravenously, such a concentration reproducibly produced a decrease in body weight of about 1.5 g over a 24-hour period (Table I), subsequent administration did not maintain the decrease in body weight (Mahony & Tisdale, 1988)
Administration of megestrol acetate alone to female NMRI mice caused an increase in body weight over a 24-hour period (Table I), together with some increase in food and water intake, this did not reach statistical significance
Summary
Pure strain female NMRI mice (age 6 to 8 weeks) were bred in our own laboratory and were fed rat and mouse breeding diet (Pilsbury, Birmingham, UK) and water ad libitum. To produce the tumour in vivo, 2 x 106 cells were injected subcutaneously into the flank, and the experiments were initiated 14 days after transplantation, when weight loss started to occur and the tumours became palpable. All experiments were performed with female animals since they are less aggressive than males, where food deprivation can occur in selected individuals. Weight-losing animals were randomised to receive either no treatment, or 100 or 300 mg kg-' megestrol acetate (generously supplied by Bristol Myers Company, Evansville, Indiana, USA) in corn oil (50 mg megestrol acetate was suspended in 3 ml of pure corn oil) administered subcutaneously in the leg. The megestrol acetate was administered daily over a 7-day period and body weight, and food and water intake were measured daily. Plasma was prepared by centrifuging whole blood in a Beckman microfuge for 30 seconds
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