[CANCERRESEARCH58, 215-218, January15, 1998] Advances in Brief Reduction of Ventral Prostate Weight by Finasteride Is Associated with Suppression of Insulin-like Growth Factor I (IGF-I) and IGF-I Receptor Genes and with an Increase in IGF Binding Protein 31 Hung Huynh,2 Raouf M. Seyam, and Gerald B Brock Lady Davis Research Institute of the Jewish General Hospital and Departments of Surgery and Medicine, McGill University, Montreal, Quebec. Canada H3T 1E2 Abstract Finasteride, a competitive and specific inhibitor of 5a-reductase, is widely used in the treatment ofsymptomatic benign prostatic hyperplasia. We demonstrate here that finasteride, when administered in an in vivo experimental system, caused ventral prostate regression. Intraprostatic dihydrotestosterone leveis decreased, whereas testosterone levels in creased in a dose-dependent manner following finasteride treatment. Fin asteride also inhibited the expression of insulin-like growth factor (IGF)-I and IGF-I receptor genes in the ventral prostate. Finasteride significantly increased IGF binding protein-3 and slightly decreased IGF binding protein-2, -4, and -5 gene expression. Because IGFs are potent mitogens for prostate epithelial cells, this newly described activity of flnasteride may contribute to its antiproliferative properties, particularly with regard to the inhibition of prostate growth seen clinically and in animal modeis. Introduction The prostate gland requires androgens for proper growth, mainte nance, and function. Men with 5a-reductase deficiency (1, 2) and men castrated when young do not develop prostate cancer (3). Androgen deprivation therapy causes characteristic changes both in the normal prostate and in prostate cancer (4, 5). The 5a-reductase enzyme is a membrane-bound protein dependent on the reduced form of NADP@ and is responsible for the conversion of testosterone to the more potent DHT3 in androgen-dependent target cells (6, 7). DHT has a greater affinity than testosterone for the androgen receptor and is thought to actively modulate prostate growth. Finasteride acts as a competitive inhibitor of 5a-reductase, resulting in the suppression of serum and intraprostatic DHT concentrations to castrate levels, with subsequent reduction in prostate size (8—10).Inhibition of 5a-reduc lane activity has been shown in vivo and in vitro (11—14).Finasteride has a safe profile with few side effects (9, 10, 15—17),making it a reasonable candidate for chemoprevention trials in the general and high-risk target populations. Although finasteride is approved for treatment of symptomatic BPH (18), the molecular mechanisms un derlying growth inhibition induced by finasteride are incompletely described. The proliferation of epithelial cells in the prostate is influenced by factors such as epidermal growth factor, TGF-a, TGF-@3,nerve growth factor, and members of the IGF and fibroblast growth factor family (19—21). Several studies have indicated that IGFs are mitogenic in prostate tumor cells and normal prostate cells (20). The prostate stroma secretes IGF-I, and the epithelial cells respond to IGFs through the interaction of these growth factors with the type 1 IGF receptor (20, 22). The principal IGF produced in the rat prostate is IGF-I, whereas in humans, the predominant species is IGF-H (reviewed in Ref. 23). IGF-I bioactivity in target tissues for IGF-I action is influenced by both serum levels of IGFs and autocrine/paracrine interactions. There is evidence that local expression of IGF-I and various IGFBPs are important in this context and are under complex physiological regulation (24, 25). Both IGF-I and IGF-II have a high affinity for IGFBPs. To date, seven IGFBPs that modulate IGF bioactivity in a complex manner have been characterized (24, 26). These binding proteins are expressed in many tissues and can be found in the conditioned media of a wide variety of cell types. Although the IGFBPs are known to influence the interaction of IGFs with their receptors, their precise physiological roles remain unclear. Both stimulatory and inhibitory effects of IGFBPs on cellular proliferation have been reported under various experimen tal conditions (27—32). Normal prostate epithelial cells have been shown to secrete IGFBP-2 and IGFBP-4, whereas stromal fibroblasts produce IGFBP-2, -3, and -4 (20, 33, 34). In the adult prostate, IGFBP-2 is expressed, while IGFBP-5 expression is repressed (19). We have shown previously that the gene expression of IGFBP-2, -3, -4, and -5 increases rapidly in the ventral prostate during castration-induced involution (35). The physiological actions of IGFBPs in prostate cells are not known. It has been hypothesized that IGFBPs attenuate the cellular response to IGF-I through the high-affinity binding of IGF-I to IGFBPs. This interaction sequesters IGF-I away from the receptor, interfering with the normal homeostatic intracellular signaling down stream of the receptor. It is also known that some IGFBPs have intrinsic bioactivity independent of IGFs (31, 36, 37). We show here that finasteride reduces ventral prostate weight in part by enhancing IGFBP-3 expression, suppressing IGF-I gene cx pression, and reducing IGF-I receptor expression. Our preliminary data, together with the antiproliferative effect of finasteride in BPH, suggest that finasteride might serve to suppress prostate cell growth by disrupting IGF autocrine/paracrine loops. Materials and Methods Received 10/24/97; accepted 12/2/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I This work was supported by Grant 778 from the Cancer Research Society and a grant from the Fonds de la Research en Sante du Quebec (to H. H.). 2 To whom requests for reprints should be addressed, at Lady Davis Research Institute, McGill University, 3755 Cote Ste Catherine Road, Montreal, Quebec, H3T IE2 Canada. Phone: (5 14) 340-8260, extension 5263; Fax: (5 14) 340-7502. 3 The abbreviations used are: DHT, dihydrotestosterone; BPH, benign prostatic hy perplasia; TGF, transforming growth factor; IGF, insulin-like growth factor; IGF-IR, IGF-I receptor; IGFBP, IGF binding protein; BW, body weight. Animals. Animals were maintained and treated according to the guide lines of the Canadian Council on Animal Care. The experimental protocol was approved by the Local Animal Care Committee. Male Sprague Dawley rats were treated with finasteride by gavage in increasing doses of 0.0, 0.1, 1.0, 10, and 100 mg/kg BW/day. Finasteride 5-mg tablets (Merck Frosst, Montreal, Quebec, Canada) were crushed and suspended in water imme diately before gavage. Each group of rats received either 1 ml of the 0. 1, 1, and 10 mg/kg BW finasteride suspensions or 3 ml of the 100 mg/kg BW dose, every day for 21 days. Control rats received only water. At the end 215 Research. on November 17, 2015. © 1998 American Association for Cancer cancerres.aacrjournals.org Downloaded from