Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693 Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol) Luciano Adorini a,∗ , Giuseppe Penna a , Susana Amuchastegui a , Chiara Cossetti a , Francesca Aquilano a , Roberto Mariani a , Benedetta Fibbi b , Annamaria Morelli b , Milan Uskokovic c , Enrico Colli a , Mario Maggi b b a BioXell, 20132 Milan, Italy Andrology Unit, University of Florence, 50139 Florence, Italy c BioXell Inc., 07110 Nutley, NJ, USA Received 30 November 2006 Abstract The prostate is a target organ of vitamin D receptor (VDR) agonists and represents an extra-renal site of 1,25-dihydroxyvitamin D3 synthesis, but its capacity to respond to VDR agonists has, so far, been almost exclusively probed for the treatment of prostate cancer. We have analyzed the capacity of VDR agonists to treat benign prostatic hyperplasia (BPH), a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic one responsible for urinary irritative symptoms, and an inflammatory component. Preclinical data demonstrate that VDR agonists, and notably BXL-628 (elocalcitol), reduce the static component of BPH by inhibiting the activity of intraprostatic growth factors downstream of the androgen receptor, and the dynamic component by targeting bladder cells. In addition, BXL-628 inhibits production of proinflammatory cytokines and chemokines by human BPH cells. These data have led to a proof-of-concept clinical study that has successfully shown arrest of prostate growth in BPH patients treated with BXL-628, with excellent safety. We have documented the anti-inflammatory effects of BXL-628 also in animal models of autoimmune prostatitis, observing a significant reduction of intra-prostatic cell infiltrate following administration of this VDR agonist, at normocalcemic doses, in mice with already established disease. These data extend the potential use of VDR agonists to novel indications that represent important unmet medical needs, and provide a sound rationale for further clinical testing. © 2006 Elsevier Ltd. All rights reserved. Keywords: Benign prostatic hyperplasia; Chronic prostatitis/chronic pelvic pain syndrome; Vitamin D analogs 1. Introduction 1,25-Dihydroxyvitamin D3 [1,25(OH)2 D3 ] binds with high affinity to the vitamin D receptor (VDR), a ligandactivated nuclear transcription factor regulating specific gene expression in target tissues. Agonist binding induces conformational changes in the VDR, which promote heterodimerization with the retinoid X receptor (RXR) and recruitment of a number of corepressor and coactivator proteins, including steroid receptor coactivator family members ∗ Corresponding author at: BioXell, Via Olgettina 58, I-20132 Milan, Italy. Tel.: +39 02 21049570; fax: +39 02 21049555. E-mail address: [email protected] (L. Adorini). 0960-0760/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2006.12.065 and a multimember coactivator complex, the D receptor interacting proteins. These coactivators induce chromatin remodelling through intrinsic histone-modifying activities, and direct recruitment of key transcription initiation components at regulated promoters. Thus, the VDR functions as an agonist-activated transcription factor that binds to specific DNA sequence elements in vitamin D responsive genes (vitamin D responsive elements, VDRE) and ultimately influences the rate of RNA polymerase II-mediated gene transcription . VDR agonists have different clinical applications, and they are currently used in the treatment of secondary hyperparathyroidism, osteoporosis, and psoriasis . More recently, the biological actions of VDR agonists have been 690 L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693 shown to extend well beyond calcium metabolism to include regulation of immune responses, angiogenesis, and growth differentiation and apoptosis of many cell types, including malignant cells . The discovery of VDR expression in most cell types of the immune system prompted a number of studies investigating the capacity of VDR agonists to modulate immune responses . VDR agonists were found to be selective inhibitors of Th1 cell development [5,6], and to inhibit directly Th1-type cytokines such as IL-2 and IFN-␥ [7,8]. 1,25(OH)2 D3 has also been shown, in some cases, to enhance the development of Th2 cells via a direct effect on naı̈ve CD4+ cells . In addition to exerting direct effects on T cell activation, VDR agonists markedly modulate the phenotype and function of antigen-presenting cells (APCs), and in particular of dendritic cells (DCs), leading them to acquire tolerogenic properties that favor the induction of regulatory rather than effector T cells . Thus, DCs appear to be primary targets for the tolerogenic properties of VDR agonists, and several immunomodulatory effects could be mediated by their capacity to inhibit the nuclear factor NF-B in DCs , a transcription factor critical for the production of proinflammatory cytokines and chemokines. In addition, inhibition of leukocyte infiltration into inflammatory sites by treatment with VDR agonists is associated with their capacity to inhibit chemokine production by cells in the target organ via inhibition of NF-B activation. This has been convincingly shown in nonobese diabetic (NOD) mice by arrest of insulitis, with block of Th1 cell infiltration into the pancreas, and inhibition of type 1 diabetes development associated with reduced chemokine production by islet cells . Based on this and additional evidence, VDR agonists are currently considered as potential drugs for the treatment of systemic autoimmune diseases  and allograft rejection [14,15]. In addition, sound epidemiological data supporting the association between vitamin D and cancer, coupled with the capacity of VDR agonists to inhibit cell growth, promote apoptosis, and favor cell differentiation have provided the basis for extensive efforts aiming at the development of these hormones as anti-cancer agents . Since, as discussed below, the prostate is a target organ of VDR agonists, their cell growth inhibitory properties and immunomodulatory activities may also find applications not only in prostate cancer, but also in the treatment of different prostate diseases unrelated to cancer, from benign prostatic hyperplasia (BPH) to non-bacterial chronic prostatitis. sion has also been detected in cultured stromal cells derived from prostate and bladder of BPH patients [17,18]. Expression of VDR in cultured human epithelial cells from prostate gland have been also described, at higher levels than in corresponding stromal cells . In addition, it is well known that malignant prostate cell lines express the VDR [20,21]. Interestingly, epithelial prostate cells express the enzyme 1␣hydroxylase, required for 1,25(OH)2 D3 synthesis , and the extra-renal synthesis of 1,25(OH)2 D3 in the prostate could have a growth-regulating role, as suggested by the marked decrease of 1␣-hydroxylase activity in prostate cancer cell lines . 3. Inhibition of prostate cell growth by VDR agonists: in vitro and in vivo evidence from experimental models Because human and rat prostate cells express VDR and respond to VDR agonists by decreasing their proliferation, we originally hypothesized  that VDR agonists could represent a novel option for the treatment of BPH. However, a problem with the therapeutic use of VDR agonists is their propensity to induce hypercalcemia and hyperphosphatemia. VDR agonists retaining biological activity but devoid of hypercalcemic side effects have been developed, and some of them approved for the treatment of secondary hyperparathyroidism and osteoporosis . Hence, non-hypercalcemic 1,25-dihydroxyvitamin D3 analogues could represent good candidates to become novel and attractive therapeutic agents for BPH. Right from the earliest experiments, we have consistently observed that VDR agonists have the ability to decrease stromal prostate cell proliferation and induce apoptosis . In particular, BXL-628 (elocalcitol, 1-␣-fluoro-25-hydroxy16,23E-diene-26,27-bishomo-20-epi-cholecalciferol, see Fig. 1) decreased testosterone (T)-stimulated human BPH cell proliferation similarly to finasteride and cyproterone acetate, and promoted BPH cell apoptosis even in the presence of growth factors . However, this analogue does not directly interfere with androgen receptor (AR) signalling because it does not affect 5(-reductase type 1 and 2 activity, it fails to bind to the AR, and it does not affect AR transcriptional activity . Molecular 2. VDR expression in prostate cells The VDR is not only present in classic target tissues as bone, bowel and kidney, but is also expressed in several other human tissues, including those derived from the urogenital sinus, as prostate and bladder . In particular, VDR expression in these tissues is quantitatively similar to classic target organs such as liver, kidney, and bone. VDR expres- Fig. 1. Structure of BXL-628 and the native hormone 1,25-dihydroxyvitamin D3. L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693 691 Fig. 2. Inhibition of prostate weight in beagle dogs treated with BXL-628. Adult beagle male dogs were treated daily orally for 9 months with vehicle alone or containing 5 g/kg BXL-628. At the end of the dosing period, and after a 2-month recovery, the prostate weight was determined, and is shown as ratio to body weight. Serum calcium levels were also determined at the end of the dosing period, and after a 2-month recovery. BXL-628 decreases prostate weight in beagle dogs, an animal species that naturally develops BPH, without increasing serum calcium levels. mechanisms involved in mediating the anti-proliferative and pro-apoptotic effects of BXL-628 were therefore hypothesized to operate downstream the AR. We have partially characterized these molecular events, which include decreased auto-phosphorylation of growth factor receptors specific for KGF and IGF-1, arrest of cell cycle progression at G1, and decreased expression of the survival factor bcl-2 . To test whether or not BXL-628 could decrease spontaneous or androgen-mediated prostate growth in vivo, we studied the rat ventral prostate, the most T-sensitive prostate area in rodents . We found that BXL-628 treatment can significantly reduce prostate growth in both naı̈ve adult rats, and in castrated, T-replaced rats, with an effect comparable to finasteride. Interestingly, at prostate growth inhibitory concentrations, BXL-628 did not affect pituitary or testicular hormone secretion and did not increase calcemia . As predicted from in vitro studies, apoptosis was evident in both epithelial and stromal prostate cells from BXL-628-treated rats, associated with increased expression of clusterin , a marker of cell death and inhibition of cell cycle progression. To further verify the inhibitory effect on prostate growth of BXL-628 in other animal species, we chronically treated male beagle dogs. After a 9-month administration of BXL-628 (5 g/kg/day per os), the prostate weight of treated dogs was substantially lower that in vehicle-treated controls, although the limited number of dogs/group did not allow reaching statistical significance (Fig. 2). Reduction of prostate weight was even more evident after a 2-month recovery (Fig. 2), suggesting a sustained effect of BXL-628 treatment. This experiment demonstrates the ability of BXL-628 to decrease prostate growth also in animal species that spontaneously develop BPH. Interestingly, even after prolonged BXL-628 administration, no increase in serum calcium levels was noted (Fig. 2). 4. Arrest of prostate growth in BPH patients by BXL-628 treatment The preclinical results reviewed above prompted a clinical investigation of BXL-628 in BPH patients. A multi-centre, double blind, randomized, placebo controlled, parallel group, phase IIa clinical study was therefore conducted to assess the efficacy and safety of BXL-628 in patients with BPH . Eligible patients (aged ≥50 years, prostate volume ≥40 ml) were randomly assigned to BXL-628 150 g daily or placebo for 12 weeks. At baseline and at the end of the study all randomized patients underwent pelvic MRI to measure prostate volume, as well as testing for uroflowmetry, serum PSA, testosterone, dihydrotestosterone and LH serum levels. A total of 119 patients were randomized: 57 patients to BXL-628 and 62 to placebo. The percentage change of prostate volume at 12 weeks was −2.9 ± 0.8 in the BXL-628 group versus +4.3 ± 0.8 in the placebo group (P < 0.0001). The estimated difference between treatments (BXL-628 minus placebo) was −7.22 (95% confidence limits between −9.27 and −5.18). These results confirm the hypothesis, predicted by our preclinical studies, that BXL-628 is able to arrest prostate growth in BPH patients. Interestingly, neither serum nor urinary calcium levels changed significantly in BXL-628 treated patients during the course of the study. Sexual side effects, often present in patients treated with 5␣-reductase inhibitors, were nearly absent in the BXL628 arm, and even lower than in the placebo arm . In this study, PSA increase was lower in the active-treated than in the placebo group, although this difference resulted not significant. Hence, results from the already ongoing doubleblind, randomized, placebo controlled, 6-month long, phase IIb trial on over 500 BPH patients are eagerly awaited. In the 12-week phase IIa trial, no difference was observed in symptom score or uroflowmetry parameters . The lack 692 L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693 of variation in these clinical parameters – in spite of a highly significant reduction of prostate growth – might be justified by the short duration of this proof-of-concept study, and by the fact that patients were not screened for symptoms but only for prostatic volume. To clarify this point, a 6-month-long phase IIb study, measuring maximum urinary flow rate and symptom severity as secondary end-points in patients with at least moderate symptomatology, is currently in progress. 5. Inhibition of prostate inﬂammation by BXL-628 An inflammatory component, revealed by prostatic inflammatory infiltrates, is observed in a large percentage of BPH surgical specimens from patients without prostatitis symptoms [28,29]. These inflammatory cells might be responsible for several biological changes leading to prostate overgrowth and for prostatitis-like symptoms associated with BPH in at least 20% of patients . In addition, accumulating evidence indicates a role for cytokines and chemokines, whose levels are increased not only in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) but also in BPH patients . Up-regulation of proinflammatory cytokines has been described in BPH patients and associated to oxidative stress and stromal tissue-remodeling . Interestingly, IL-1␣ and IL-8 are known to induce KGF and FGF-2 expression in cultured BPH cells [33,34], and IL-8 can directly promote proliferation of BPH cells . A chronic inflammatory response might thus trigger transdifferentiation of resident stromal cells, resulting in a sustained prostate overgrowth through its growth factors, a situation similar to wound healing . CP/CPPS (chronic non-bacterial prostatitis, NIH category III) is a highly prevalent syndrome of suspected autoimmune origin . Based on the marked inhibitory activity of the VDR agonist BXL-628 on basal and growth factorinduced proliferation of human prostate cells, and on its potent anti-inflammatory properties in different models, we have tested its capacity to treat experimental autoimmune prostatitis (EAP). EAP was induced in non obese diabetic (NOD) mice, a strain genetically prone to develop different autoimmune diseases, by injection of mouse prostate homogenate in CFA . BXL-628 was administered orally 5 dose/week at 100 g/kg from day 14 to 28 post immunization. Administration of BXL-628, at non hypercalcemic doses, for 2 weeks in already established EAP inhibits significantly the intra-prostatic cell infiltrate, leading to a profound reduction in the number of CD4+ and CD8+ T cells, B cells, macrophages and dendritic cells. Immunohistological analysis demonstrates decreased cell proliferation and increased apoptosis. In addition, decreased production of the proinflammatory cytokines IFN-␥ and IL-17 is observed in prostate-draining lymph node T cells from BXL-628-treated NOD mice stimulated by TCR ligation or prostate antigens (Penna et al., manuscript in preparation). Thus, BXL-628, at non hypercalcemic doses, is able to interfere with key pathogenic events in already established EAP in the NOD mouse. These data support the autoimmune pathogenesis of CP/CPPS, and indicate that treatment with the VDR agonist BXL-628 may prove clinically beneficial in this syndrome. To establish a clinical proof of concept, a randomized, doubleblind, placebo controlled, parallel group study to determine the effect of BXL-628 in CP/CPPS patients is ongoing. Analysis of several proinflammatory cytokines and chemokines in seminal fluids indicate IL-8 concentration, a secondary endpoint in the trial, as a reliable surrogate marker for treatment efficacy. Thus, the anti-inflammatory and immunomodulatory properties of BXL-628, demonstrated in vitro in BPH cell cultures and in vivo in an experimental model of autoimmune prostatitis, could turn out to be beneficial both in BPH and in CP/CPPS patients. 6. Conclusions The preclinical and clinical data reviewed here show that BXL-628 is able to inhibit prostate growth, and indicate its ability to control prostate inflammation. Different mechanisms of action account for the capacity of BXL-628 to reduce the static component of BPH, from induction of apoptosis in prostate cells to inhibition of intra-prostatic growth factor activity downstream the AR. In addition, BXL-628 could affect the dynamic component of BPH by targeting bladder cells , and have beneficial effects also by controlling the inflammatory response in the prostate of BPH patients. Ongoing clinical studies will show whether or not this drug is also able to reduce symptoms and ameliorate flow parameters in BPH-affected individuals. The pronounced effects of BXL-628 on bladder smooth muscle cells and its antiinflammatory properties are promising features for beneficial effects also on lower urinary tract symptoms. In addition, the anti-inflammatory properties of BXL-628, demonstrated in an experimental model of autoimmune prostatitis, could be translated to the treatment of CP/CPPS. Indeed, as CP/CPPS and BPH are two conditions characterized by both prostate inflammation and cell proliferation, treatment with BXL-628 may prove efficacious in both indications. Acknowledgment Supported in part by the European Community grant INNOCHEM to L.A. References  C. Carlberg, Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands, Recent Results Cancer Res. 164 (2003) 29–42.  V. Pinette, Y.K. Yee, B.Y. Amegadzie, S. Nagpal, Vitamin D receptor as a drug discovery target, Mini Rev. Med. Chem. 3 (3) (2003) 193–204. L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693  S. Nagpal, S. Na, R. Rathnachalam, Noncalcemic actions of vitamin D receptor ligands, Endocr. Rev. 26 (5) (2005) 662–687.  L. Adorini, Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases, Int. Immunopharmacol. 2 (7) (2002) 1017–1028.  J.M. Lemire, D.C. Archer, L. Beck, H.L. Spiegelberg, Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions, J. Nutr. 125 (1995) 1704S–1708S.  F. Mattner, S. Smiroldo, F. Galbiati, M. Muller, P. Di Lucia, P.L. Poliani, G. Martino, P. Panina-Bordignon, L. Adorini, Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25dihydroxyvitamin D(3), Eur. J. Immunol. 30 (2) (2000) 498–508.  I. Alroy, T. Towers, L. Freedman, Transcriptional repression of the interleukin-2 gene by vitamin D3 : direct inhibition NFATp/AP-1 complex formation by a nuclear hormone receptor, Mol. Cell. Biol. 15 (1995) 5789–5799.  M. Cippitelli, A. Santoni, Vitamin D3 : a transcriptional modulator of the IFN-␥ gene, Eur. J. Immunol. 28 (1998) 3017–3030.  A. Boonstra, F.J. Barrat, C. Crain, V.L. Heath, H.F. Savelkoul, A. O’Garra, 1alpha,25-dihydroxyvitamin D3 has a direct effect on naive CD4(+) T Cells to enhance the development of Th2 cells, J. Immunol. 167 (9) (2001) 4974–4980.  L. Adorini, G. Penna, N. Giarratana, A. Roncari, S. Amuchastegui, K.C. Daniel, M. Uskokovic, Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands, J. Steroid Biochem. Mol. Biol. 89–90 (1–5) (2004) 437–441.  M.D. Griffin, N. Xing, R. Kumar, Vitamin D and its analogs as regulators of immune activation and antigen presentation, Annu Rev Nutr. 23 (2003) 117–145.  N. Giarratana, G. Penna, S. Amuchastegui, R. Mariani, K.C. Daniel, L. Adorini, A Vitamin D analog downregulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development, J. Immunol. 173 (2004) 2280–2287.  L. Adorini, Intervention in autoimmunity: the potential of vitamin D receptor agonists, Cell Immunol. 233 (2) (2005) 115–124.  L. Adorini, 1,25-Dihydroxyvitamin D3 analogs as potential therapies in transplantation, Curr. Opin. Invest. Drugs 3 (10) (2002) 1458–1463.  B.N. Becker, D.A. Hullett, J.K. O’Herrin, G. Malin, H.W. Sollinger, H. DeLuca, Vitamin D as immunomodulatory therapy for kidney transplantation, Transplantation 74 (8) (2002) 1204–1206.  S. Nagpal, S. Na, R. Rathnachalam, Non-calcemic actions of vitamin D receptor ligands, Endocr. Rev. 26 (5) (2005) 662–687.  C. Crescioli, A. Morelli, L. Adorini, P. Ferruzzi, M. Luconi, G.B. Vannelli, M. Marini, S. Gelmini, B. Fibbi, S. Donati, D. Villari, G. Forti, E. Colli, K.E. Andersson, M. Maggi, Human bladder as a novel target for vitamin D receptor ligands, J. Clin. Endocrinol. Metab. 90 (2) (2005) 962–972.  C. Crescioli, P. Ferruzzi, A. Caporali, R. Mancina, A. Comerci, M. Muratori, M. Scaltriti, G.B. Vannelli, S. Smiroldo, R. Mariani, D. Villari, S. Bettuzzi, M. Serio, L. Adorini, M. Maggi, Inhibition of spontaneous and androgen-induced prostate growth by a nonhypercalcemic calcitriol analog, Endocrinology 144 (7) (2003) 3046–3057.  D.M. Peehl, R.J. Skowronski, G.K. Leung, S.T. Wong, T.A. Stamey, D. Feldman, Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells, Cancer Res. 54 (3) (1994) 805–810.  A.V. Krishnan, D.M. Peehl, D. Feldman, The role of vitamin D in prostate cancer, Recent Results Cancer Res. 164 (2003) 205–221.  S. Marchiani, L. Bonaccorsi, P. Ferruzzi, C. Crescioli, M. Muratori, L. Adorini, G. Forti, M. Maggi, E. Baldi, The vitamin D analogue                  693 BXL-628 inhibits growth factor-stimulated proliferation and invasion of DU145 prostate cancer cells, J. Cancer Res. Clin. Oncol. 132 (6) (2006) 408–416. G.G. Schwartz, L.W. Whitlatch, T.C. Chen, B.L. Lokeshwar, M.F. Holick, Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3, Cancer Epidemiol. Biomarkers Prev. 7 (5) (1998) 391–395. T.C. Chen, L. Wang, L.W. Whitlatch, J.N. Flanagan, M.F. Holick, Prostatic 25-hydroxyvitamin D-1alpha-hydroxylase and its implication in prostate cancer, J. Cell Biochem. 88 (2) (2003) 315–322. C. Crescioli, M. Maggi, G.B. Vannelli, M. Luconi, R. Salerno, T. Barni, M. Gulisano, G. Forti, M. Serio, Effect of a vitamin D3 analogue on keratinocyte growth factor-induced cell proliferation in benign prostate hyperplasia, J. Clin. Endocrinol. Metab. 85 (7) (2000) 2576–2583. H.H. Malluche, H. Mawad, N.J. Koszewski, Update on vitamin D and its newer analogues: actions and rationale for treatment in chronic renal failure, Kidney Int. 62 (2) (2002) 367–374. C. Crescioli, P. Ferruzzi, A. Caporali, M. Scaltriti, S. Bettuzzi, R. Mancina, S. Gelmini, M. Serio, D. Villari, G.B. Vannelli, E. Colli, L. Adorini, M. Maggi, Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia, Eur. J. Endocrinol. 150 (4) (2004) 591–603. E. Colli, P. Rigatti, F. Montorsi, W. Artibani, S. Petta, N. Mondaini, R. Scarpa, P. Usai, L. Olivieri, M. Maggi, BXL628, a novel vitamin D3 analog arrests prostate growth in patients with benign prostatic hyperplasia: a randomized clinical trial, Eur. Urol. 49 (1) (2006) 82–86. J.C. Nickel, J. Downey, I. Young, S. Boag, Asymptomatic inflammation and/or infection in benign prostatic hyperplasia, BJU Int. 84 (9) (1999) 976–981. J. Morote, M. Lopez, G. Encabo, I.M. de Torres, Effect of inflammation and benign prostatic enlargement on total and percent free serum prostatic specific antigen, Eur. Urol. 37 (5) (2000) 537–540. J.C. Nickel, M. Elhilali, G. Vallancien, Benign prostatic hyperplasia (BPH) and prostatitis: prevalence of painful ejaculation in men with clinical BPH, BJU Int. 95 (4) (2005) 571–574. G. Kramer, M. Marberger, Could inflammation be a key component in the progression of benign prostatic hyperplasia? Curr. Opin. Urol. 16 (1) (2006) 25–29. K.L. Lee, D.M. Peehl, Molecular and cellular pathogenesis of benign prostatic hyperplasia, J. Urol. 172 (5 Pt 1) (2004) 1784–1791. D. Giri, M. Ittmann, Interleukin-1alpha is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia, Am. J. Pathol. 157 (1) (2000) 249–255. D. Giri, M. Ittmann, Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign prostatic hyperplasia, Am. J. Pathol. 159 (1) (2001) 139–147. P. Castro, D. Giri, D. Lamb, M. Ittmann, Cellular senescence in the pathogenesis of benign prostatic hyperplasia, Prostate 55 (1) (2003) 30–38. G. Untergasser, E. Plas, G. Pfister, E. Heinrich, P. Berger, Interferongamma induces neuroendocrine-like differentiation of human prostate basal-epithelial cells, Prostate 64 (4) (2005) 419–429. M.A. Pontari, M.R. Ruggieri, Mechanisms in prostatitis/chronic pelvic pain syndrome, J. Urol. 172 (3) (2004) 839–845. V.E. Rivero, C. Cailleau, M. Depiante-Depaoli, C.M. Riera, C. Carnaud, Non-obese diabetic (NOD) mice are genetically susceptible to experimental autoimmune prostatitis (EAP), J. Autoimmun. 11 (6) (1998) 603–610.
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