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Influence of N-Methyl-N-Nitrosourea, Testosterone, and N-(4-Hydroxyphenyl)-all-trans-retinamide on Prostate Cancer Induction in Wistar-Unilever Rats¹

Life Sciences Department, IIT Research Institute, Chicago, Illinois 60616 [D. L. M., K. V. N. R., L. D.]; Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland 20892 [V. E. S., R. A. L., G. J. K.]; and Nelson Institute of Environmental Medicine and Department of Urology, New York University Medical Center, Tuxedo, New York 10987 [M. C. B.]

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.

¹ Supported by Contract N01-CN-85097-08 from the National Cancer Institute, Department of Health and Human Services. A preliminary report of these results was presented at the annual meeting of the American Association for Cancer Research, Toronto, Ontario, Canada, in March 1995.

² To whom requests for reprints should be addressed, at Life Sciences Department, IIT Research Institute, 10 West 35 Street, Chicago, IL 60616.

Received 12/22/97. Accepted 5/19/98.

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