Maspin sensitizes prostate cancer cells to doxazosin-induced apoptosis.

Maspin is a mammary serine protease inhibitor or serpin with tumor suppressive and antiangiogenic activity that inhibits tumor motility, invasion and metastasis, at least by its actions on cell membrane and extracellular matrix (ECM) proteins. Previous studies documented that the quinazoline-derived alpha1-adrenoceptor antagonist doxazosin affects the attachment and migration of prostate cancer cells. In this study, we investigated the effect of maspin overexpression on the apoptotic/antiadhesion response of prostate cancer cells to doxazosin. The response of maspin-overexpressing clones of human prostate cancer cells DU-145 to doxazosin was evaluated by determining cell viability, apoptosis and cell proliferation on the basis of the trypan blue exclusion assay/methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, Hoechst staining and caspase-3 activation, and [(3)H]thymidine incorporation assay. Vascular endothelial growth factor (VEGF), transforming growth factor betaRII (TGFbetaRII), Smad4 (a TGFbeta intracellular effector) and bax expression was evaluated at the mRNA and protein level using reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The effect of doxazosin on cell attachment of maspin-expressing prostate cancer cells was evaluated on collagen- and fibronectin-coated plates. Cell migration was assessed using the wounding assay. In response to tumor necrosis factor-related apoptosis-inducing ligand, DU-145-maspin expressing cells undergo apoptosis, via poly(ADP-ribose) polymerasecleavage and caspase-3 activation. DU-145-maspin cells exhibited higher sensitivity to doxazosin and an earlier temporal activation of caspase-3. The number of apoptotic cells detected in response to doxazosin was significantly higher compared to the neo control (P<0.0001). Doxazosin resulted in dramatic downregulation of the 189 isoform of VEGF in maspin transfectants, while a fivefold induction of Smad4 mRNA expression was detected in those cells after 24 h of treatment. Maspin overexpression in prostate cancer cells resulted in an increased ability to attach to ECM-coated plates, and doxazosin treatment considerably antagonized this effect by decreasing the attachment potential to collagen and fibronectin. The present study supports the ability of maspin to enhance the apoptotic threshold of prostate cancer cells to the quinazoline-based alpha1-adrenoceptor antagonist doxazosin. These findings may have therapeutic significance in the development of antiangiogenic targeting by doxazosin and derivative agents for advanced prostate cancer.

A rare case of renal oncocytoma associated with erythrocytosis: case report.

BACKGROUND: Oncocytomas are benign tumors of the kidney that are usually diagnosed postoperatively due to differential diagnostic problems from renal cell carcinoma. Although the latter are neoplasms that have been associated with erythrocytosis in 3.5% of cases, there are no reports in the literature about a similar occurrence in oncocytomas. CASE PRESENTATION: In this case report we present a unique case of a right lower pole oncocytoma associated with erythrocytosis. Erythrocytosis subsided after partial nephrectomy. CONCLUSION: Erythrocytosis can sometimes occur in association with renal oncocytomas.

The role of alpha-blockers in the management of prostate cancer.

Prostate cancer is the second most common cause of cancer death in men in the US. Patients with prostate cancer are initially treated with surgical resection, radiation or antiandrogen therapy. After an initial remission, however, the majority of prostate tumours evolve into a highly aggressive, metastatic androgen-independent state, for which successful therapy has not yet been established. During the past few years, new perspectives have emerged towards the development of preventive and therapeutic approaches for prostate cancer. Quinazoline-based alpha(1)-blockers have been shown to have antitumour efficacy against prostate cancer cells in inducing apoptosis and anoikis via an alpha(1)-adrenoceptor-independent mechanism. Specifically, doxazosin and terazosin can induce apoptosis, inhibit invasion and migration of prostate cancer and endothelial cells, and reduce their adhesion potential to extracellular matrix components, thus enhancing their susceptibility to anoikis. This review discusses recent evidence suggesting the apoptotic efficacy of quinazoline-based alpha(1)-adrenoceptor antagonists, doxazosin and terazosin and speculates on the therapeutic promise of these drugs as novel antitumour agents against prostate cancer. From a drug discovery perspective, separation of the effect of doxazosin on apoptosis in prostate cancer cells from its original pharmacological activity in normal prostate cells, will provide a molecular basis in developing a novel class of apoptosis-inducing agents through lead optimisation.

Unilateral urinothorax can occur contralateral to the affected kidney.

Urinothorax is a rare cause of transudative pleural effusion with biochemical characteristics of urine, usually secondary to obstructive uropathy. Urine usually moves into the pleural space from the retroperitoneal or peritoneal space via diaphragmatic lymphatics or an anatomical diaphragm defect. A total of approximately 70 cases have been previously described in the literature, and in the vast majority of cases urinothorax is unilateral and ipsilateral to the side of obstructive uropathy, trauma or malignancy. This report describes a rare case of unilateral urinothorax occurring contralateral to the side of obstruction.

Urinothorax-an underdiagnosed cause of acute dyspnea: report of a bilateral and of an ipsilateral urinothorax case.

Urinothorax (UT) is a rare and often undiagnosed condition, defined as the presence of urine in the pleural cavity due to the retroperitoneal leakage of urine accumulation, known as urinoma, into the pleural space. UT usually is a transudative pleural effusion that presents in patients with obstructive uropathy and it may occur following surgical procedures in the ureter or kidney such as ESWL, PCNL, and URS. Its diagnosis requires a high degree of clinical suspicion since the respiratory symptoms tend to be absent or mild and the urological signs tend to dominate. However, UT may rarely present with severe and acute dyspnea as well. The objectives of this study are to describe two new cases of this rare entity, a bilateral case and an ipsilateral case focusing on the side that occurs according to the affected renal insult, and to alert the physicians to include UT in their differential diagnosis of pleural effusions especially in patients with recent urinary tract disorders.

Bilateral synchronous occurrence of three different histological types of renal tumor: a case report.

INTRODUCTION: Renal cell carcinomas account for 85% of all renal neoplasms. With the introduction of modern imaging modalities, there has been an increased diagnosis of renal tumors. Recent studies have shown that partial nephrectomy can be as safe as radical nephrectomy for smaller renal tumors. Renal cell carcinomas are usually unilateral, however, they can be bilateral in 2% to 4% of sporadic cases and considerably more common in familial cases. CASE PRESENTATION: In this case report, we describe an unusual case of two bilateral synchronous chromophobe renal cell carcinomas accompanied by an oncocytoma and an angiomyolipoma, that were all treated by open partial nephrectomy. CONCLUSIONS: To the best of our knowledge, this is the first case report on the synchronous occurrence of bilateral chromophobe renal cell carcinomas associated with an oncocytoma and an angiomyolipoma.

Solitary multilocular cystic renal cell carcinoma in adults: diagnostic problems, pathological features and treatment.

Multilocular cystic renal cell carcinoma represents a rare clinical entity in adults. This report describes the authors' experience with seven tumours, including the first two tumours in the literature diagnosed during pregnancy.

Application of dorsal preputial island flap in meatoplasty.

INTRODUCTION AND OBJECTIVES: Meatal stenosis usually presents in adults with a history of urethral trauma or inflammation or as a complication after hypospadias repair. The objective of this study is to present the correction of meatal stenosis using a preputial island flap, created on the dorsal surface of the penis. METHODS: During the last 3 years 12 patients were subjected to meatoplasty using a preputial flap. A meatotomy was performed and a preputial island flap was raised on the dorsal surface of the penis, that was brought to the ventral surface and anastomosed to the opened fossa navicularis. RESULTS: Mean follow-up is 22.3 (range 6-40) months and urethral meatus remains normal with good caliber in routine examination mainly with dilators and uroflowmetry. CONCLUSIONS: The described method was based on the on-lay preputial island flap procedure (Duckett's method) for correction of anterior hypospadias. The cosmetic result is excellent and normal penile morphology and function are well preserved.

Effect of terazosin on tissue vascularity and apoptosis in transitional cell carcinoma of bladder.

OBJECTIVES: To present a pilot study to determine whether the alpha1-adrenoceptor antagonist terazosin can induce apoptosis in transitional cell carcinoma (TCC) of the bladder, similar to the effect seen with prostate cancer. The alpha1-adrenoceptor antagonist terazosin has recently been shown to induce apoptosis in prostate cancer cells both in vitro and in vivo and to reduce prostatic tissue vascularity by potentially affecting endothelial cell adhesion. METHODS: The records of 24 men who underwent radical cystectomy for TCC of the bladder at the Lexington Veterans Affairs Medical Center were reviewed. The control group consisted of 15 men who were never exposed to terazosin. The study group consisted of 9 men who were treated with terazosin before cystectomy. Sections of the bladder tumor and normal trigone were subjected to immunohistochemical analysis for microvessel density, endothelial cell CD31 expression, and apoptosis detection (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling), as well as high-molecular-weight cytokeratin staining. RESULTS: A significant reduction in tissue vascularity (14.0 versus 19.2, P <0.05) and a significant increase in the apoptotic index (3.0% versus 1.7%, P <0.05) was detected in terazosin-treated bladder tumors compared with untreated bladder tumors. Most TCC specimens (80%) exhibited strong and consistently uniform immunostaining for high-molecular-weight cytokeratin staining. CONCLUSIONS: These results suggest that terazosin reduces tumor vascularity and induces apoptosis in TCC of the bladder. Additional studies with more patients are necessary to reach definitive conclusions. However, considering the proven apoptotic action of terazosin in prostatic tissue, this study may have implications for the use of terazosin in the treatment of bladder TCC.

Apoptotic impact of alpha1-blockers on prostate cancer growth: a myth or an inviting reality?

BACKGROUND: Pharmacological manipulation or genetic targeting of the major apoptosis regulators, such as bcl-2, caspases, and inhibitors of apoptosis (IAPs), represent clinically attractive avenues towards effective therapeutic strategies for advanced prostate cancer. A wealth of evidence established the alpha(1)-adrenoceptor antagonists to be clinically effective in relieving the symptoms associated with benign prostatic hyperplasia (BPH) by relaxing prostatic smooth muscle tone. This action alone however does not fully account for the long-term clinical response to these drugs in BPH patients. METHODS: Experimental and retrospective clinical studies provided new evidence supporting a differential growth-suppressing function of two alpha(1)-adrenoceptor antagonists against prostate cancer, independent of an alpha(1)-adrenoceptor mechanism. RESULTS: The quinazoline-based antagonists, doxazosin and terazosin, induce apoptosis, inhibit cell adhesion to the extracellular matrix (by activating anoikis), and prevent cell invasion and migration of prostate tumor epithelial cells and vascular endothelial cells. Tamsulosin, a sulphonamide-based, clinically effective alpha(1)-adrenoceptor antagonist for BPH treatment, fails to exert a similar apoptotic action against prostate cells. Furthermore, at pharmacologically relevant doses, doxazosin suppresses benign and malignant prostate growth in in vivo experimental models. The effect is characterized by three intriguing features: (a) it is mediated by an alpha(1)-adrenoceptor-independent action, (possibly related to the quinazoline nucleus); (b) it is targeted at the apoptotic process without affecting cell proliferation; and (c) the elevated apoptotic index correlated with symptom score improvement in BPH patients. CONCLUSIONS: This evidence challenges conventional knowledge of the mechanism of action of alpha(1)-adrenoceptor antagonists, and points to a new therapeutic value for these drugs by providing a differential molecular basis for their anti-tumor efficacy. The present review focuses on the characterization of the apoptotic/anti-angiogenic effect of quinazoline-based alpha(1)-adrenoceptor antagonists against prostate cancer cells and discusses the clinical significance of this action in the prevention and treatment of prostate cancer.