Caloric Restriction and 7,12-Dimethylbenz(a)anthracene-induced Mammary Tumor Growth in Rats: Alterations in Circulating Insulin, Insulin-like Growth Factors I and II, and Epidermal Growth Factor1

Caloric restriction (CR) inhibits many neoplastic diseases in rodents, yet the biochemical mechanism(s) for these effects are poorly understood. We have examined the effects oÃ-ad libitum (AL) feeding with 25 or 40% CR on the promotion of 7,12-dimethylbenz(a)anthracene-induced mam mary tumorigenesis in virgin female Sprague-Dawley rats. Further, we have also studied the influence of chronic CR on temporal alterations in circulating insulin, insulin-like growth factor I/somatomedin C, insulinlike growth factor H/multiplication-stimulating activity, and epidermal growth factor levels at 0, 1, 3, 5, 11, and 20 weeks in carcinogenand vehicle-treated animals. Tumor incidence and multiplicity were markedly inhibited (/' < 0.05) with increasing CR. Fasting serum insulin-like growth factor I/somatomedin C levels exhibited a significant acute decline with CR at 1 and 3 weeks, but were comparable to AL-fed controls throughout the remainder of the 5-month study, despite continued differ ences in weight gain between AL and CR rats. Levels of insulin-like growth factor H/multiplication-stimulating activity exhibited no discern ible pattern in relation to CR. Serum insulin levels showed age-dependent increases, but were affected by increasing CR at all time points. Insulin levels were significantly ( /' < 0.05) reduced in 40% CR rats from 3 weeks onward compared to controls, while 25% CR resulted in nonsignificant (/' < 0.07) reductions throughout the study. No significant differences in growth factor levels were observed between 7,12-dimethylbenz(<z)anthraceneand vehicle-treated rats. Circulating epidermal growth factor was not detectable in any treatment group regardless of the nature or duration of the dietary regimen, time of blood collection, or subsequent tumor-bearing status. These data suggest that decreased serum insulin-like growth factor I/ somatomedin C and insulin levels with CR and their complex interactions in vivo may play a role in the inhibition of mammary tumor promotion byCR.