New therapy modalities for the treatment of advanced prostate cancer based on peptide analogues are reviewed.
Agonists and antagonists of luteinising hormone-releasing hormone (LHRH) lead to androgen deprivation, but direct effects on tumours may also play a role. Radiolabeled somatostatin analogues can be targeted to tumours expressing receptors for somatostatin and have been successfully applied for the localization of these tumours. Tumoural LHRH, growth hormone-releasing hormone (GHRH), and bombesin/gastrin–releasing peptide (BN/GRP) and their receptors appear to be involved in the proliferation of prostate cancer. On the basis of the recent advances in the understanding of the role of neuropeptides in tumour growth and progression, new therapeutic modalities are being developed that are based on antagonists of GHRH and of BN/GRP, which inhibit growth factors or their receptors. Another promising approach for the therapy of prostate cancer consists of the use of cytotoxic analogues of LHRH, bombesin, and somatostatin, which can be targeted to receptors for these peptides in prostate cancers and their metastases.
New promising forms of hormone therapy and targeted chemotherapy may improve therapy of advanced stage prostate cancer.
Keywords: Prostate cancer, Hormone therapy, Peptide analogues, Targeted chemotherapy, Androgen deprivation.
In 1941, Huggins and Hodges established that carcinoma of the prostate is frequently dependent on testosterone and introduced androgen deprivation as therapy for advanced prostate cancer  and . Endocrine therapy for prostate cancer has included bilateral orchiectomy, administration of estrogens and antiandrogens, and even hypophysectomy or adrenalectomy .
However, bilateral orchiectomy is associated with important psychological and social impact. Treatment with estrogens is limited by its serious cardiovascular side-effects. Side-effects of antiandrogens are cardiovascular toxicity, hepatotoxicity, and mammotropic effects  and .
In 1982, Schally et al introduced a radically different hormonal therapy for prostate cancer, based on the use of highly potent synthetic agonistic analogues of luteinising hormone-releasing hormone (LHRH) for the treatment of advanced prostate cancer , , , , and . The isolation and elucidation of the structure of hypothalamic LHRH, the synthesis of its analogues, and the demonstration that chronic administration of agonists of LHRH causes downregulation of LHRH receptors in the pituitary, leading to an inhibition of follicle-stimulating hormone (FSH) and LH release, and a concomitant decrease in testosterone production , , and  offered a new method for androgen-deprivation therapy in prostate cancer patients. This treatment option enabled many men to avoid physical, emotional and psychological effects of surgical castration.
The efficacy of therapy with agonists of LHRH in men with advanced stage prostate cancer was first demonstrated in a clinical trial in patients with stage C and stage D prostate cancers. A fall in testosterone levels and marked subjective and objective improvement was described  and .
Depot formulations of LHRH agonists such as buserelin, leuprolide, goserelin and triptorelin have been developed for more efficacious and more convenient treatment of patients with prostate cancer . Phase 3 studies of LHRH agonists versus surgical castration demonstrated no difference in survival between the two therapies . Multiple phase 3 studies have demonstrated that all preparations have a similar efficacy . LHRH agonists have side-effects: Impotence, loss of libido, hot flashes, anemia, weight gain, hair loss, and osteopenia have been described and can be explained by the androgen deficiency , , and . There is recent evidence that androgen deprivation with LHRH agonists is associated with diabetes and cardiovascular disease .
Initial treatment with LHRH agonists causes a surge of LH release, with a corresponding increase in testosterone levels. This testosterone surge, known as the flare phenomenon, can result in a transient increase in prostate cancer growth, urinary obstruction, worsening of bone pain, and paralysis in patients with extensive metastasis to the spinal cord. The flare phenomenon can be prevented by short-term administration of antiandrogens .
A major advantage over surgical castration is that medical castration with agonists of LHRH is reversible. This fact seems to be important for those patients for whom intermittent androgen blockade is considered. Multiple phase 3 trials have documented that intermittent androgen blockade could decrease side-effects of continuous androgen blockade . LHRH agonists have been evaluated in multiple clinical settings in advanced disease as well as in adjuvant and neoadjuvant settings. Combination therapy with LHRH analogues and antiandrogens (maximal androgen blockade) revealed no survival benefit .
LHRH agonists have also been used prior to or following various local treatments in patients with clinically localised prostate cancer and at high risk for disease recurrence . Thus indications for the treatment with LHRH agonists include, besides T3 metastatic prostate cancer, patients with rising prostate-specific antigen (PSA) levels after surgery or radiation therapy , , and .
As androgen-dependent prostate cancer constitutes about 70% of all cases of prostate neoplasms  and , LHRH agonists are currently the preferred primary treatment for advanced prostate cancer , , and .
2. Antagonists of LHRH
Antagonists of LHRH have been developed to cause an immediate and dose-related inhibition of LH and FSH by competitive blockade of the LHRH receptors. Antagonists of LHRH have also been shown to downregulate pituitary LHRH receptors in rat pituitaries  and .
Experimental work showed that LHRH antagonist cetrorelix decreases the levels of testosterone and inhibits growth of androgen-dependent cancers . LHRH has also been described as tumoural growth factor, and receptors for LHRH have been found in prostate cancer specimens  and . Thus, antagonists of LHRH could be superior to agonists because of better inhibition of LHRH as a tumoural growth factor. Administration of cetrorelix also resulted in a decrease of messenger RNA (mRNA) for epidermal growth factor receptors (EGFR) and of insulin-like growth factor (IGF)-II in PC-3 and DU-145 prostate cancer xenografted into nude mice  and .
To date several potent LHRH antagonists are available for the clinical use in patients. Cetrorelix was the first LHRH antagonist given marketing approval and, thus, became the first LHRH antagonist available clinically. It has been shown to be safe and effective in inhibiting LH and sex-steroid secretion in vivo and in clinical studies , , and . Treatment of patients with advanced prostate carcinoma and benign prostate hyperplasia (BPH) with cetrorelix showed a lowering of serum testosterone to castration levels, a decrease in elevated PSA levels, as well as marked clinical improvement  and .
Patients with paraplegia due to metastases to the spinal cord showed neurological improvement during therapy with cetrorelix . Cetrorelix may be especially beneficial for patients with prostate cancer and metastases to the spinal chord, bone marrow and other sites, in whom LHRH agonists cannot be used as single drugs because of the possibility of disease flare  and . Sustained release formulations of cetrorelix are under development by Zentaris Gmbh (Frankfurt/Main, Germany) and are being tested in phase 1 and phase 2 clinical trials in prostate cancer and BPH patients  and .
Clinical trials with other LHRH antagonists such as abarelix and azaline have been performed. Recently new LHRH antagonists such as degarelix have been introduced. They are characterised by improved sustained-release preparations, pharmacokinetic properties such as bioavailability, solubility, intra- or intermolecular hydrogen bond-forming capacity, and ability to bind carrier proteins  and . Treatment with azaline B was reported to lead to potent pituitary-gonadal axis suppression and extremely low anaphylactic activity .
Abarelix was compared with leuprolide acetate in a phase 3 randomised trial . Medical castration was achieved in 75% of the abarelix group by day 15, compared with 10 percent of patients in the leuprolide group. The percentage decrease in PSA was significantly greater after treatment with abarelix on day 15 . Because this study does not have long-term follow-up, it is not possible to determine if abarelix and leuprolide will provide identical rates of disease control.
Experimental and clinical data indicate that LHRH antagonists such as cetrorelix and abarelix can be useful for the therapy of prostate cancer or BPH. Various growth factors such as LHRH, EGF, IGF-I and -II, vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) are known to be involved in prostate cancer growth, and some contribute to androgen-independent growth  and . Because tumour inhibition of cetrorelix is also linked to a downregulation of EGF and EGF-R and IGF-I, antagonists of LHRH could open a new perspective for prostate cancer treatment .
3. New approaches to treat androgen-independent prostate cancer based on peptide analogues
Hormone ablation therapy induces a first-line response in patients with prostate cancer, but the duration of remission is limited and androgen-independent re-growth of prostate cancer is observed in most patients . All available treatment options are palliative, and no efficacious therapy exists for patients who relapse the first-line hormonal treatment based on androgen deprivation. Most chemotherapeutic regimens provide essentially only a minor benefit with respect to survival or quality of life, although new chemotherapy schedules based on the efficacy of docetaxel may provide a survival advantage , , and . On the basis of recent advances in the understanding of the role of neuropeptides and growth factors in the growth, neoplastic transformation, and progression of prostate cancer, antagonists of bombesin/gastrin-releasing peptide (BN/GRP), somatotropin, and growth hormone releasing hormone (GHRH) have been developed  and . Because hormone receptors for somatostatin, BN/GRP, and LHRH are expressed on prostate cancers, these hormone receptors can be used for targeting cytotoxic peptide conjugates selectively to the tumour. The development of new cancer therapies based on peptide analogues offers a promising strategy for the management of advanced prostate cancer.
4. Antagonists of BN/GRP
The tetradecapeptide hormone bombesin was isolated in 1971 from frog skin (Bombina bombina). After the isolation of the hormone bombesin, two mammalian bombesin-like peptides were characterised, gastrin-releasing peptide (GRP), which consists of 27 amino acids and neuromedin B , , , and . GRP is widely distributed in lung and gastrointestinal tracts. It is produced in small cell lung cancer (SCLC), breast, prostatic, and pancreatic cancer, and functions as a growth factor  and . Four receptor subtypes associated with the bombesin-like peptide family have been identified , , , , and . BN/GRP peptides were shown to bind selectively to the G-protein–coupled receptors on the cell surface, stimulating the growth of various malignancies in murine and human cancer models. Thus, it has been proposed that the secretion of BN/GRP by neuroendocrine cells might be responsible for the development and progression of prostate cancer to androgen independence . BN/GRP was also shown to increase in vitro proliferation and invasiveness of androgen-independent prostate cancer  and . Specific binding sites for BN/GRP are present in androgen-independent cell lines and in surgical specimens of prostate cancer , , and .
The involvement of bombesin-like peptides in the pathogenesis of a wide range of human tumours, their function as autocrine/paracrine tumoural growth factors, and the high incidence of BN/GRP receptors in various human cancers  and  prompted the design and synthesis of BN/GRP receptor (GRPR) antagonists such as RC-3095, RC-3940-II,and RC-3950 for therapeutic use  and . Bombesin antagonists were shown to inhibit various experimental BN/GRP receptor–positive cancers, including PC-3, DU-145, MDA-PCa-2b prostate cancers , , , and . Antiproliferative effects of BN/GRP antagonists are thought to be mediated by the blockade of mitogenic stimuli of BN/GRP and the downregulation of receptors for BN/GRP and EGF , , and .
Inhibition of tumour growth of PC-3 and DU-145 prostate cancers is exerted by suppressing the expression of tumoural growth factors such as VEGF and basic fibroblast growth factor as well as the receptors for EGF and related human EGF receptor (HER)-2 and -3 . Investigating the signalling transduction pathways implicated in the antiproliferative effect of BN/GRP antagonists, we found that protein kinase C (PKC) isoforms and mitogen-activated protein kinase (MAPK), as well as the expression of the early oncogene c-jun may be involved in its mechanisms .
5. Somatostatin analogues
Somatostatin is a peptide hormone consisting of 14 amino acids. It is found in δ cells of the pancreas as well as in hypothalamic and other gastrointestinal cells, and acts as a paracrine/autocrine hormone and “antigrowth factor.” Somatostatin and its octapeptide analogues have many biological actions and inhibit a large variety of cellular functions  and . Potent octapeptide analogues of somatostatin including octreotide (Sandostatin)  and  and vapreotide (RC-160) , , and  have been developed during the past 20 yr  and . Five distinct receptor subtypes for somatostatin (sst1–5) have been cloned and characterised  and . Sandostatin and vapreotide have been used for the treatment of acromegaly and endocrine tumours of the gastroenteropancreatic system, including carcinoid tumours , , and . Long- acting depot formulations of Sandostatin LAR for once-monthly administration are available for clinical use , , and .
Native somatostatin shows similar high affinity to receptor subtypes sst1–5, but the synthetic octapeptides such as RC-160 and octreotide bind preferentially to sst2 and sst5. RC-160 also binds to sst3  and . Somatostatin analogues inhibit growth of experimental prostate cancers directly by blocking the receptors for somatotropin and indirectly by decreasing hepatic IGF-I secretion. , , , and . However, attempts to use somatostatin analogues for the therapy of human cancers have produced few beneficial effects , , and . Poor therapeutic results with octapeptide somatostatin analogues are likely due to the fact that, in various cancers, there is a loss of gene expression for sst2, which is the preferred subtype for these analogues .
Clinical responses with the combination therapy of the somatostatin analogue lanreotide, LHRH analogue triptorelin (Decapeptyl), and dexamethasone in patients with relapsed metastatic prostatic cancer stage D3 have also been reported . The expression of sst5 and sst3 should make possible therapy with somatostatin analogues labeled with various radioisotopes or cytotoxic somatostatin analogues.
6. Antagonists of GHRH
GHRH is produced by various human tumours, including prostate cancer, and seems to exert an autocrine/paracrine stimulatory effect on tumours , , , , , , and . GHRH ligand is present in various human cancers, indicating that it may be a local tumoural growth factor. This observation suggests the presence of a stimulatory loop based on GHRH and splice variants (SVs) or pituitary type of GHRH receptors in diverse tumours. Antagonistic analogues of human GHRH were designed to inhibit the secretion of GH from the pituitary by blocking the binding of hypothalamic GHRH to GHRH receptors  and . GHRH antagonists bind with a high affinity to pituitary receptors for GHRH and inhibit the release of GH in vitro and in vivo . Various potent antagonistic analogues of GHRH were synthesised for clinical applications in the field of cancers dependent on GHRH and IGF-I and -II . GHRH antagonists inhibit a large variety of human tumours xenografted into nude mice, including androgen-independent prostate cancers , , , , and . The effects of GHRH antagonists are in part exerted indirectly through inhibition of the secretion of pituitary growth hormone and the resulting reduction in levels of serum IGF-I, which is mainly of hepatic origin . However, recent evidence indicates that direct inhibitory effects of GHRH antagonists on some cancers, resulting in the reduction of tumoural IGF-II levels in the tumour tissue , , and , are even more important for tumour growth inhibition than serum IGF-I suppression , , , , and . Direct inhibitory effects of GHRH antagonists appear to be mediated by the splice variants of GHRH receptors (GHRH-Rs) that have been found on various tumours  and . Thus recently, four SVs of GHRH-R have been described, of which SV1 has the highest structural homology to pituitary GHRH-R and likely plays a role in tumour growth . The expression of GHRH and truncated SVs of GHRH-Rs was shown in surgical specimens from patients with locally advanced prostate cancer  and in experimental human prostate cancers , , , and . GHRH antagonists seem to act through SV receptors and decrease synthesis of IGF-I, IGF-II, VEGF, and FGF , , and . GHRH antagonists strongly inhibited the growth and metastatic behaviour of prostatic cancers xenografted subcutaneously, orthotopically or intraosseously into nude mice  and . The maximal binding capacity of EGFRs and their mRNA levels in PC-3 and DU-145 tumours were decreased after treatment with GHRH antagonists . A recent study  suggests that antagonists of GHRH inhibit the growth of androgen-independent prostate cancer by affecting intracellular signalling mechanisms of PKC, MAPK and c-jun.
The therapeutic use of synthetic peptides has been restricted so far by their availability. Strategies used to increase drug delivery in vivo include the enhancement of stability and circulation time in the bloodstream, targeting of specific tissues or cells, and facilitation of intracytoplasmic delivery . GHRH antagonists selected for clinical development should possess high binding affinities and exert biological effects on both the pituitary and the tumoural SV receptors for GHRH . Further development of GHRH antagonists should lead to potential therapeutic agents for various cancers.
7. Targeted chemotherapy with peptide analogues
The use of conventional chemotherapy is restricted by its toxicity . Targeted chemotherapy was designed to improve the effectiveness of cytotoxic drugs and decrease peripheral toxicity. The receptors for peptide hormones on tumour cells can serve as targets for peptide ligands that can be linked to various cytotoxic agents. Cytotoxic analogues of LHRH, somatostatin, and bombesin that can be targeted to various tumours were synthesised, and their effect was evaluated on human experimental prostate cancers .
Because the peptide receptors are variably expressed in diverse cancers, a careful determination of receptors and their subtypes in tumour tissue is required before therapy with cytotoxic analogues .
7.1. Cytotoxic analogues of LHRH
Eighty-six percent of specimens of human prostate adenocarcinomas exhibited high-affinity binding sites for LHRH and expressed mRNA for LHRH receptors , , , , and . The high incidence of specific receptors for LHRH on tumour cells prompted the development of a new class of targeted antitumour agents by linking various cytotoxic radicals to LHRH analogues.
The first effective cytotoxic LHRH hybrid molecule was synthesised in the late 1980s by Nagy and Schally  by linking [D-Lys6] LHRH to doxorubicin (DOX). Subsequently an improved targeted cytotoxic LHRH analogue was developed by the same group. This new compound consisted of [D-Lys6] LHRH covalently linked to intensely potent derivative 2-pyrrolino-DOX (AN-201), which is 500–1000 times more active in vitro than its parent compound. AN-201 can also be characterised as a noncardiotoxic and non–cross-resistant derivative of DOX . These two conjugates, AN-152, consisting of [D-Lys6]LHRH linked to DOX-14-O-hemiglutarate, and AN-207, its super active counterpart containing 2-pyrrolino-DOX showed potent tumour inhibition of human experimental prostate cancers .
In all experimental prostate cancer models, targeted chemotherapy with AN-207 proved to be more effective and less toxic compared with its cytotoxic radical AN-201. Therapy with AN-201 caused only a minor reduction in tumour volume but resulted in higher mortality and morbidity, as shown by body weight loss and white blood cell counts due to toxicity. The stronger tumour inhibition and lower toxicity of AN-207, compared with AN-201, could be attributed to a more selective delivery to tumour cells , , , and . Therapy with AN-207 inhibited tumour proliferation of experimental prostate cancers in nude mice by 80–90% . Blockade of LHRH receptors with LHRH agonist triptorelin nullified the effects of AN-207. Treatment with AN-207, but not with AN-201, decreased Bcl-2/Bax ratio in DU-145 tumours and Bcl-2 in LuCaP-35 tumours, indicating an increase in apoptotic activity . Cytotoxic LHRH analogues AN-207 and AN-152 were shown to have high-affinity binding to LHRH receptors on prostate tumours , , , and . In addition, both analogues retained the powerful cytotoxic activities of their respective cytotoxic radicals.
Because LHRH receptors are present in high levels in LH-producing cells of the anterior pituitary, therapy with AN-152 and AN-207 will result in the accumulation of DOX and AN-201, respectively, in this organ. Treatment with targeted cytotoxic LHRH analogue AN-207 was demonstrated to cause selective damage to the gonadotroph cells in rat pituitaries 1 wk after injection. However, the pituitary function completely recovered 1 wk later . Only a transient decrease in the mRNA for LHRH receptors in rat pituitary was observed after the injection of AN-207 . The lack of toxicity of AN-207 on the pituitary cells, which were slowly proliferating, may be explained by the properties of the cytotoxic radical, AN-201, which is a powerful DNA-intercalating agent that selectively kills rapidly proliferating cell types such as cancer cells and cells of the bone marrow. Because receptors for LHRH are expressed in only low concentrations in most normal tissues, other targeting-related side-effects are not expected after treatment with AN-207 or AN-152 . Signs of myelotoxicity were observed in all of our studies in animals that received AN-201, but only in a few cases in animals that received targeted chemotherapy. In fact, the dose-limiting toxicity of AN-207 will probably be myelotoxicity, caused by AN-201 that is released by carboxylesterase enzymes from AN-207 in the circulation. Because of the low activity of the carboxylesterase enzymes in humans, we can expect few adverse side-effects of DOX or AN-201 in patients  and .
Our work suggests the concept that targeted chemotherapy based on cytotoxic LHRH analogues should be more efficacious and less toxic than the corresponding systemic chemotherapeutic regimens and should permit an escalation of doses. Targeted cytotoxic analogues of LHRH can be used for the treatment of advanced prostate cancer after relapse and might be also considered for primary therapy of patients with advanced prostate cancer. AN-152 is in clinical phase 2 trials in Germany.
7.2. Cytotoxic somatostatin analogues
Somatostatin receptors are used for the localisation of some tumours and metastases by scanning techniques  with radiolabelled analogues of somatostatin, such as 111In-octreotide (OctreoScan). Octreascan is used clinically for the localization of neuroendocrine tumours such as carcinoids and SCLC as well as non-neuroendocrine tumours such as breast cancer, renal cancer, and brain tumours .
High-affinity binding sites for somatostatin analogues were found to be present in 65% of primary prostate cancer specimens, and the expression of sst2 on 14% and sst5 on 64% of samples tested was demonstrated  and . Schally et al , , , and  developed a series of novel targeted cytotoxic somatostatin conjugates that consist of carrier analogues RC-121 and RC-160 coupled to DOX or 2-pyrrolino-DOX. Of these hybrid cytotoxic conjugates, analogue AN-238, containing AN-201, was demonstrated to be most effective in various experimental cancer models . A strong tumour inhibition of experimental androgen-independent human prostate cancers expressing sst2 and sst5 xenografted into nude mice was described after treatment with AN-238 . AN-238 reduced final tumour volumes by more than 60%, whereas AN-201 at an equimolar dose was ineffective. In a metastatic model of PC-3, the treatment with AN-238 inhibited the weight of orthotopic tumours, producing a 77% reduction. In addition, no retroperitoneal or distant metastases could be observed 4 wk after start of the therapy with AN-238  and . In addition four injections of AN-238 virtually arrested the proliferation of DU-145 androgen-independent prostate cancer in nude mice. AN-201 was less effective and toxic.
Because receptors for somatostatin are found especially in the rapidly proliferating cells of the gastrointestinal tract, some side-effects of treatment with cytotoxic and radiolabelled analogues of somatostatin are expected. However, none of the studies in which rodents were treated with AN-238 showed specific toxicity to the gastrointestinal tract, the pituitary, or the kidneys. Tests on basal or GHRH-stimulated GH levels before ending of the experiments showed no significant changes in the pituitary function . These results indicate that the possible damage inflicted by AN-238 to somatostatin receptor–positive normal tissues is limited. Because AN-238 is less harmful to slowly proliferating cells such as the pituitary cells, the damage caused by AN-238 to the pituitary is transient. In the case of the rapidly proliferating cells of the gastrointestinal cells, it is likely that the undifferentiated resting cells can replace the damaged cells. Our findings on the toxicity of AN-238 are in accordance with clinical observations that there were no or only low-grade toxicities to the kidneys and the pituitary after therapy with radionuclide analogues of somatostatin  and . Our results suggest that chemotherapy with AN-238 targeted to somatostatin receptors on tumours might improve the management patients with advanced prostate cancer.
7.3. Cytotoxic analogues of BN/GRP
The application of radiolabelled bombesin analogues for tumour detection has been proposed . It has been demonstrated that 111In-labeled analogues of bombesin allow visualisation of tumours expressing specific BN/GRP binding sites. Because BN/GRP receptors are expressed in various tumours including prostate cancers and their metastases, and BN/GRP plays a major role as a tumoural growth factor, targeted chemotherapy with cytotoxic analogues of BN/GRP such as AN-215 could be considered. Nagy and Schally  synthesised targeted cytotoxic bombesin conjugates using bombesin antagonists as carriers. Thus, superactive cytotoxic bombesin conjugate AN-215 was prepared by linking radical AN-201 to the amino terminal of des-D-Tpi-RC-3095. This analogue was tested in various in vivo tumour models.
High-affinity receptors for BN/GRP were detected on specimens of human prostate cancer in experimental human prostate cancers , , , and . The cytotoxic bombesin analogue AN-215 was tested in experimental human prostate cancers and produced a reliable tumour inhibition of 81–91% . The cytotoxic radical AN-201 was less effective and more toxic. Administration of BN antagonist RC-3095 prior to AN-215 blocked the receptors for BN/GRP and inhibited the effects of AN-215 . Therapy with AN-215, but not with AN-201, decreased the ratio of Bcl-2/Bax in DU-145 tumours and the expression of antiapoptotic Bcl-2 in LuCaP-35 tumours . Similarly to receptors for somatostatin, receptors for BN/GRP are widely distributed in the body, including the gastrointestinal tract. To estimate toxicity related to GRP receptors, we evaluated the effect of AN-215 on the GRP-stimulated serum gastrin level in mice before termination of the experiments. No permanent damage to the gastrin-releasing function of the gastrointestinal cells in either study was found . Because bombesin receptors are present on metastatic prostate cancers, targeted chemotherapy with AN-215 should benefit patients with advanced prostatic carcinoma who no longer respond to androgen deprivation.
Conflicts of interest
The authors have nothing to disclose.
Some original experimental work reviewed herein was supported by the Medical Research Service of the Veteran Affairs Department (to A.V.S.).
Various scientific and clinical contributions of countless colleagues are gratefully acknowledged.
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a Department of Urology University of Vienna, Vienna, Austria
b Endocrine Polypeptide and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education and Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA
© 2007 European Association of Urology, Published by Elsevier B.V.