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Prostatic hyperplasia (BPH) is a very common disease in elderly men and is characterized by abnormal proliferation of the stromal and epithelial cells of the prostate. The observation that BPH often occurs in association with chronic inflammation has led to the examination of the possibility that platelet-derived growth factor (PDGF), which is released in response to inflammation, may be an etiological factor in the genesis of the disease. It has been shown that cultured cells derived from human prostatic tissue express high affinity PDGF-beta receptors based on receptor binding and cross-linking studies with [125I]-PDGF-BB. The experiments presented below demonstrate that PDGF receptors are activated in response to the growth factor and that mitogenesis is induced. PDGF-BB treatment of cultured human prostate cells derived from patients with BPH activates the signal transduction pathway of the PDGF receptor as shown by the presence of several phosphoproteins in antiphosphotyrosine immunoprecipitates, including autophosphorylation of the PDGF receptor. Phosphatidylinositol (PI) 3-kinase activity is also increased in cells stimulated with PDGF. The addition of PDGF-BB to the medium causes of variable but dose-dependent increase in [3H]-thymidine incorporation. This paper describes the first demonstration that PDGF is a potent mitogen for human cells derived from patients exhibiting prostatic hyperplasia, and also demonstrates that the cellular response to PDGF-BB is heterogenous in a manner that is consistent with the varying degree of hyperplasia and inflammation clinically and histologically in the tissue specimens.

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Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation, growth, and maintenance of the mammalian prostate. Production of DHT from testosterone is catalyzed by two distinct membrane-bound steroid 5a-reductase [5a-reductase; 3-oxo-5a-steroid A4-dehydrogenase; 3-oxo-5a-steroid:(acceptor) AW-oxidoreductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign prostatic hyperplasia (BPH), a disease that occurs almost universally in males, is characterized by obstructive and irritative urinary voiding symptoms and has been associated with an overproduction of DHT. Recently, steroidal inhibitors of 5a-reductase type 2 have been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of 5a-reductase type 1, LY191704 {8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo[f]quinolin-3(2H)-one}. This compound was identified based on its capacity to inhibit 5a-reductase activity in a human genital skin fibroblast cell line (Hs68). Surprisingly, LY191704 is inactive when tested in freshly isolated prostate cells obtained from subjects with BPH, whereas previously described 4-azasteroids are active. LY191704 is, however, a potent inhibitor of the 5a-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5a-reductases expressed from transfected cDNAs in simian COS cells indicates that LY191704 is a specific noncompetitive inhibitor of the human 5a-reductase type 1. Taken together, the results suggest that prostate cells have the capacity to express both 5a-reductase isozymes and that LY191704 may be useful in treatment of human endocrine disorders associated with overproduction of DHT by 5a-reductase type 1.Prostatic hyperplasia is an age-related nonmalignant enlargement of the prostate that can result in development of obstructive and irritative urinary voiding symptoms (1, 2). For >100 years, prostatectomy has been used to treat benign prostatic hyperplasia (BPH) and is now the most common surgery performed in men >65 years old (3). Although prostatic surgery has been greatly refined, it still remains a significant cause of morbidity in elderly men (4). Recent attempts have, therefore, sought to develop pharmacological approaches for the treatment of BPH with the principal focus being on the development of agents that affect the underlying mechanisms leading to prostatic hyperplasia.Male sexual tissues show a profound dependence on the continuous presence of androgens for normal growth and function (5-8). Whereas testosterone is produced by the testes, dihydrotestosterone (DHT) is produced from testosterone in tissues by an NADPH-dependent reaction catalyzed by the membrane-bound enzyme Sa-reductase [3-oxo-The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. 5a-steroid A4-dehydrogenase; 3-oxo-5a-steroid:(acceptor) A4-oxidoreductase, EC 1.3.99.5] (9). Testosterone...

Benign prostatic hyperplasia (BPH) is characterized by varying degrees of epithelial and stromal hyperplasia in association with inflammation. Although androgens are known to be important for the growth and function of the prostate, their role in the development of BPH is unclear. The release of platelet-derived growth factor (PDGF) in response to inflammation suggests that PDGF may participate in the development of BPH. Cultured prostate cells derived from patients with BPH were examined for the presence of functional PDGF and androgen receptors. The cells expressed PDGF receptors and responded to PDGF stimulation by the activation of the PDGF signal transduction pathway and a dose-dependent stimulation of cell proliferation. Even though the cells expressed androgen receptors, dihydrotestosterone failed to elicit a mitogenic response. While the role of androgens in BPH remains unclear, these results suggest that inflammation and, specifically, PDGF may be important etiologic factors in the development of BPH.