Recent evidence suggests that enhancement of carcinogenesis in animals fed high fat diet may be related to elevated calorie intake or improved calorie utilization in these animals. Since a mechanism for the increase in cancer rate by a high fat diet has not been identified for any site at which dietary fat enhances cancer, it is possible that effects of high fat diet in providing calories or influencing calorie utilization may be important in the observed effects on carcinogenesis. However, early investigations on dietary fat and calorie effects on skin carcinogenesis indicated that high fat intake enhanced tumor development at various levels of calorie intake. Since the two-stage model of skin carcinogenesis is an excellent means for assessing effects on initiation (by dimethylbenzanthracene, DMBA) and promotion (by 12-0-tetradecanoylphorbol-13-acetate, TPA) of epithelial cancers and because dietary fat and calorie effects on the model have not been reported, the following studies are proposed: 1) determination of the effect of dietary fat on two-stage carcinogenesis. Low and high fat diets will be fed to SENCAR mice during DMBA initiation only, or during promotion with or without TPA. 2) Assessment of an effect of dietary restriction on two stage-skin carcinogenesis by 2 methods: a) restriction of a complete diet to 60% of ad libitum consumption, or b) allowing access to a diet providing 60% of the calories but equivalent amounts of vitamins, minerals and fiber as consumed by the ad libitum group. 3) Comparison of the effect on two-stage skin carcinogenesis of removal of fat calories with removal of carbohydrate calories. 4) Measurement of the effects of each of the dietary fat and restriction protocols on oncogene expression during mouse skin tumorigenesis. Preliminary work indicated that Ha-ras expression elevation was an early event in two-stage skin carcinogenesis and dietary effects on this event have not been reported. 5) Study the influence of the dietary fat and restriction protocols on membrane lipids and protein kinase C (PKC) activity. Recent reaults demonstrated increased PKC activity in the particulate fraction of basal epidermal cells from mice fed a high fat-high calorie diet and decreased levels of PKC activity in the soluble fraction of cells from these animals, in comparison with mice fed low fat diets.
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