EFFECT OF CALORIC RESTRICTION ON PREMALIGNANT AND MALIGNANT STAGES OFMAMMARY CARCINOGENESIS

Caloric restriction has documented beneficial effects on numerous dise ases including cancer, yet the mechanism(s) that accounts for these wi de ranging benefits is unknown. Part of the difficulty in defining mec hanisms has been the long-term nature of experimental protocols in whi ch these beneficial effects have been observed and the inherent diffic ulty of investigating mechanisms in such studies, The experiments repo rted were designed: (1) to determine if caloric restriction would inhi bit mammary carcinogenesis in a model for this disease process that is 35 days in duration; (2) to determine if progression from pre-maligna nt to malignant stages of mammary carcinogenesis was affected by calor ic restriction; and (3) to explore whether the effects of caloric rest riction were associated with changes in adrenal function. Mammary carc inogenesis was induced in female Sprague-Dawley rats by the i.p. admin istration of 1-methyl-1-nitrosourea (50 mg/kg body weight) at 21 days of age. Rats were randomized to one of four dietary treatment groups: ad libitum fed, or restriction of food intake to 90, 80 or 60% of the ad libitum intake. Rats were palpated for detection of mammary tumors and all mammary lesions excised at necropsy were histologically classi fied. Twenty-four-hour collections of urine were obtained at weekly in tervals throughout the 35-day experiment. Urine was assayed for cortic osterone by direct radioimmunoassay. Caloric restriction resulted in b oth a dose dependent prolongation of latency to palpable carcinomas (P < 0.01) and a reduction in final incidence of mammary cancer; the dos e response was linear (P < 0.05). The percentage of pre-malignant mamm ary lesions in a group increased with increasing degree of caloric res triction, whereas the percentage of carcinomas decreased (P < 0.05). T he level of cortical steroid increased linearly with increasing calori c restriction (P < 0.01) an effect that was not attenuated over time. Poisson regression analyses with the number of cancers per rat as the dependent variable, level of caloric restriction as the independent va riable and urinary cortical steroid excretion as a co-variate were per formed. These analyses indicated that the variation in cancers per rat , irrespective of the treatment group to which an animal was assigned, could be accounted for by urinary cortical steroid excretion (P < 0.0 5); i.e. urinary cortical steroid excretion was an independent predict or of an animal's carcinogenic response. The data reported in this stu dy support the use of a short term model to study the mechanism(s) by which caloric restriction inhibits mammary carcinogenesis and point to both a stage in the disease process, the conversion of pre-malignant to malignant cells, and a target tissue (adrenal gland) and chemical s pecies (adrenal cortical steroid) that may be involved in mediating th e protective effects of energy restriction. These data indicate the fe asibility of identifying a chemical basis for the protective effect of caloric restriction that is independent of energy restriction per se and this, in turn, indicates that it may be possible to circumvent the practical problem of implementing a program of chronic energy restric tion in human populations, yet still achieve the wide-ranging health b enefits of such a program.