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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

The Wistar Institute of Anatomy and Biology [B. A. R., D. M. K., D. K.]; Department of Pediatrics, University of Pennsylvania School of Medicine, and Division of Endocrinology/Diabetes, Children's Hospital of Philadelphia, Philadelphia [R. W. F.]; and the Department of Biochemistry and Biophysics, University of Pennsylvania [B. A. R.]; Philadelphia, Pennsylvania 19104

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 of ad libitum (AL) feeding with 25 or 40% CR on the promotion of 7,12-dimethylbenz(a)anthracene-induced mammary 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, insulin-like growth factor II/multiplication-stimulating activity, and epidermal growth factor levels at 0, 1, 3, 5, 11, and 20 weeks in carcinogen- and vehicle-treated animals. Tumor incidence and multiplicity were markedly inhibited (P < 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 differences in weight gain between AL and CR rats. Levels of insulin-like growth factor II/multiplication-stimulating activity exhibited no discernible 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 (P < 0.05) reduced in 40% CR rats from 3 weeks onward compared to controls, while 25% CR resulted in nonsignificant (P < 0.07) reductions throughout the study. No significant differences in growth factor levels were observed between 7,12-dimethylbenz(a)anthracene- and 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 by CR.

¹ Supported by a training grant (CA-09485) from NIH; Best Foods, a division of CPC International, Inc.; Grants CA-38981 and CA-43856 from the National Cancer Institute; and a Research Career Award (HL-00734) from NIH.

² To whom requests for reprints should be addressed, at The Wistar Institute of Anatomy and Biology, 3601 Spruce Street, Philadelphia, PA 19104.

³ Present address: University of Rochester School of Medicine, Department of Pediatrics, Rochester, NY 14642.

Received 9/23/88. Revised 1/18/89. Accepted 5/ 4/89.

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