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Chemopreventive Activity of Tamoxifen, N-(4-Hydroxyphenyl

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Chemopreventive Activity of Tamoxifen, N-(4-Hydroxyphenyl [CANCERRESEARCH55. 5621-5627. December 1. 1995] Chemopreventive Activity of Tamoxifen, N-(4-Hydroxyphenyl)retinamide, and the Vitamin D Analogue Ro24-5531 for Androgen-promoted Carcinomas of the Rat Seminal Vesicle and Prostate @ M. Scott 2 Mario A. Anzano,' Michael V. Miriam R. Anver, Darlene M. Green, Mark W. Shrader, Daniel L. Logsdon, Craig L. Driver, Charles C. Brown, Christopher W. Peer, Anita B. Roberts, and Michael B. Sporn4 Laboratory of Chemoprevention (M. S. L, M. A. A., C. W. P.. A. B. R., M. B. S.] and Biometry Branch (C. C. B.]. National Cancer Institute, NIH, Bethesda, Maryland 20892; Department of Veterinary Pathology. Armed Forces Institute of Pathology, Washington DC 20306 (M. V. S.]; and Science Applications International Corporation-Frederick, Frederick, Maryland 21702 (M. R. A.. D. M. G., M. W. S., D. L L, C. L D.] ABSTRACT genitally deficient in Sa-reductase, which converts testosterone to Sa-dihydrotestosterone, have poorly developed prostates and have not We evaluated the ability of dietary N-(4-hydroxyphenyl)retinamide; been reported to develop prostatic carcinoma (9). Likewise, men who lcv,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24- are castrated before the age of 40 have a much lower than expected 5531); and tamoxifen to inhibit the development of androgen-promoted carcinomas of the accessory sex organs of male Lobund-Wistar rats. incidence rate for prostatic carcinoma as they age (10). With this in Invasive carcinomas ofthe seminal vesicle (SV) and anterior prostate (AP) mind, a chemoprevention strategy aimed at inhibiting androgen-pro were induced in Lobund-Wistar rats with three different combinations of moted carcinogenesis may be effective in reducing the incidence of initiator [N-nitroso-N-methylurea (NMU)] and promoter [testosterone invasive prostatic carcinoma. propionate (TP)]: (a) high-dose NMU (30 mg/kg) + high-dose TP (20 mg A major obstacle for carcinogenesis and chemoprevention studies via implant every 2 months); (b) high-dose NMU + low-dose TP (10 mg for prostate carcinoma has been the development of a suitable animal implanted every 2 months); or (c) low-dose NMU (15 mg/kg) + low-dose model (I 1, 12). The LW5 rat has been shown to develop tumors in the TP. During the period of TP administration, rats were fed a diet supple “prostatecomplex―after initiation with NMU and promotion with TP mented with either N-(4-hydroxyphenyl)retinamide (1 or 2 mmol/kg diet), (13,14).AlthoughmanyofthesetumorsarisefromtheSV,whichhas Ro24-5531 (L25 or 2.5 nmol/kg diet), tamoxifen (0.5 or 5 mg(kg diet), or vehicle alone. After sacrifice at 8.5 or 11 months, the prostate-seminal been considered a major drawback to this model, it nevertheless vesicle complex from each rat was processed in toto and histologically represents a defined example of androgen-promoted carcinoma. Using staged as to the extent of tumor involvement. In animals given low-dose the LW rat model, we have evaluated three potential chemopreventive TP, all three agents were significantly effective at reducing the incidence agents: 4-HPR (fenretinide); Ro24-S53l (a synthetic vitamin D asia of invasive carcinomas of the SV and, to a lesser degree, the AP. Of the logue); and the estrogen response modifier tamoxifen. three agents, tamoxifen given in high dose (5 mg/kg) had the strongest The potential efficacy of these agents for chemoprevention has activity, reducing the occurrence of invasive SV carcinomas from 72—83% been reported in a variety of systems. In clinical studies, retinoids in controls to 6% (P 0.0001) and the occurrence of invasive AP have been shown to have chemopreventive activity for carcinomas carcinomas from 50—72%to18—22%(P< 0.05). arising in the head and neck (15, 16). In the laboratory, 4-HPR has shown chemopreventive activity for carcinomas of the mouse urinary INTRODUCTION bladder (17) and the rat mammary gland (18) and prostate (19). Dietary 4-HPR has been reported to decrease the incidence and mass Over the last 25 years, despite aggressive efforts toward earlier of ras- and myc-induced carcinomas in a mouse prostate reconstitu detection and treatment, the mortality rate for prostatic carcinoma has tion model (20). Several prostatic carcinoma cell lines have receptors steadily increased (1). The high mortality rate, now the second highest for vitamin D (21, 22), and the active form of vitamin D, 1,25-D3, has among cancers of males in the United States, is due largely to the fact growth-inhibitory activity for these cell lines in serum-based cell that the majority of patients have advanced disease beyond the con culture growth assays (21), as well as for primary cultures derived fines of the prostate by the time of diagnosis (2). The identification of from normal or carcinomatous human prostates (23). A variety of androgens as the major regulator of prostatic epithelial proliferation, vitamin D analogues (deltanoids) have also been shown to inhibit both in the normal prostate and in prostatic carcinomas, was originally growth in a similar fashion (24, 25) and to stimulate the secretion of hoped to offer a target for therapeutic intervention for such advanced prostate-specific antigen in the human LNCaP prostate carcinoma cell tumors (3—5).However, in practice, the concept of “totalandrogen line (24). 1,25-D3 has also shown some chemopreventive activity for ablation―therapy has found only limited success (2, 4). As treatment colon adenocarcinomas induced with l,2-dimethylhydrazine (26). failures for advanced carcinoma continue to frustrate clinicians, more The estrogen response modifier tamoxifen has for some time been emphasis has recently been focused on possible strategies to prevent used in the hormonal therapy of breast carcinomas in women. There the development of invasive prostatic carcinoma (6 —8).Testosterone are no reports of its use in males for prostate cancer. However, it has or its more active metabolite (Sce-dihydrotestosterone) is recognized as the major promoter for prostatic malignancy. As such, men con been shown that the promoting activity of testosterone for prostate carcinogenesis in rats is potentiated by E2 (27). This potentiation may be a result of up-regulation of androgen receptor in the prostate by E@ Received 6/19/95; accepted 9/26/95. The costs of publication of this article were defrayed in part by the payment of page (28, 29), an increased Vmaxfor nuclear 5a-reductase (30), or an as yet charges. This article must therefore be hereby marked advertisement in accordance with unidentified mechanism. 18 U.S.C. Section 1734 solely to indicate this fact. I These authors are all considered first authors on the work described herein. 2 To whom requests for reprints should be addressed, at Department of Pathology, Box 5 The abbreviations used are: LW, Lobund-Wistar, 4-HPR, N-(4-hydroxyphenyl)reti B-216,UniversityofColoradoMedicalCenter,Denver,CO80262. namide (fenretinide); Ro24-5531, la,25-dihydroxy-l6-ene-23-yne-26,27-hexafiuoro 3 Present address: Stine-Haskell Research Center, DuPont Merck Pharmaceutical cholecalciferol; l,25-D3, la,25-dihydroxycholecalciferol (1,23-dihydroxyvitamin D3); Company, Newark, DE 19714. E2, estradiol; NMU, N-nitroso-N-methylurea; TP, testosterone propionate; SV, seminal 4 Present address: Department of Pharmacology, Dartmouth Medical School, Hanover, vesicle; AP, anterior prostate; DLP, dorsolateral prostate; VP, ventral prostate; TGF-@, NH 03755. transforming growth factor 13. 5621 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1995 American Association for Cancer Research. CHEMOPREVENTIONOF ANDROGEN.PROMOTEDCARCINOMA MATERIALS AND METHODS LW rats were obtained and housed at the National Cancer Institute Fred crick Cancer Research and Development Center (Frederick, MD) from an original breeding stock provided as a gift by Dr. Morris Pollard (University of Notre Dame).Three animals per cage were housed in polycarbonatecages with Sani-Chips bedding in a controlled environment with lighting between 6 a.m. and 6 p.m. At all times, water and diet were provided ad !ibitum.The animals were 3 months old at the beginning of the experiments. The procedure for tumor induction was the same as described previously (14), with the following exceptions. Three different combinations of the carcinogen (NMU) and promoter (TP) were used. In Experiment A, the i.v. dose of NMU (Ash Stevens, Detroit, MI) was 30 mg/kg body weight, whereas the implanted dose of TP (Sigma Chemical Co., St. Louis, MO) was 20 mg. In Experiment B, the implanted dose of TP was decreased to 10 mg, whereas the dose of NMU remained at 30 mg/kg body weight. In Experiment C, the dose of NMU was decreased to 15 mg/kg body weight, and the implanted dose of TP was reduced to 10 mg. The TP implants were replaced every 2 months for the duration of the experiments. In each of the 3 experiments, a total of 126 animals were divided into 7 treatment groups of 18 animals each: group 1, control diet; group 2, Ro24-5531 (2.5 nmollkg diet, Hoffmann-LaRoche, Nutley, NJ); group 3, Ro24-553l (1.25 nmol/kg diet); group 4, 4-HPR (2 mmol/kg diet, R. W. Johnson Pharmaceutical Research Institute, Spring House, PA); group 5, 4-HPR (I mmol/kg diet); group 6, tamoxifen (5 mg/kg diet, Sigma); and group 7, tamoxifen (0.5 mg/kg diet). All the test compounds were dissolved in ethanol and incorporated into Purina 5002 diet (Purina Mills, Inc., St. Louis, MO), along with Neobee M-5 oil (37.5 mi/kg diet, Stepan Chemical, Maywood, NJ) and Tenox 5 (1 mI/kg diet, Eastman Chemical, Kingsport, TN). Control diet consisted of ethanol vehicle, along with Neobee oil and Tenox 5. At the end of the experimental time period (either 8.5 or 11 months), the animals were euthanized with CO2.
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