Preventive and Enhancing Effects of Retinoids on the Development of Naturally Occurring Tumors of Skin, Prostate Gland, and Endocrine Pancreas in Aged Male ACI/segHapBR Rats2

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Abstract
The effects of dietary retinoids on the development of naturally occurring tumors in retired breeder male AChegHapBR rats were investigated. Groups of rats (21–25 mo of age, an age when early neoplasms first appear and tumor incidences are generally low) were fed diets containing 1 of 3 retinoids—all-trans-N-4-(4-hydroxyphenyl)retinamide (4-HPR), 783 mg/kg diet; all-trans-N-(4-pivaloyloxyphenyl)retinamide (4-PPR), 951 mg/kg; or all-trans-4-N-(2-hydroxyethyl)retinamide (2-HER), 687 mg/kg—or control diet for up to 54 weeks (average, 33 wk). Rats were maintained until less than 20% remained and the experiment was terminated. Contributing causes of death were determined, and a complete necropsy was performed for each rat. There was no difference between the retinoid-treated rats and control rats in the average age at death (30–31 mo) or in the average experimental survival time (29–35 wk), in the proportions of tumor-bearing rats (95.6–10O%), or in the average number of organs with tumor per rat (2.1–2.5). The incidences of pancreatic islet cell adenoma and skin tumors were significantly different between control and some retinoid-treated groups. 4-PPR and 2-HER significantly enhanced pancreatic islet cell adenoma yields (P<.025 and 0.05, respectively) whereas 4-HPR significantly inhibited epithelial and connective tissue skin tumor yields (P<.025). Incidences of skin and prostate tumors were lower than in controls, but not significantly, in rats receiving 4-PPR and 2-HER. Most of the islet cell adenomas were shown, by avidin-biotin-peroxidase complex immunocytochemistry, to be insulinomas. 4-HPR would seem to be the most effective retinoid in the group, inasmuch as it prevented skin tumor development, may have slightly decreased the incidence of prostate tumors, and did not enhance islet cell tumor incidence.

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