Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.

alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases.

Concealed umbilical stoma: long-term evaluation of stomal stenosis.

PURPOSE: The technique of forming a concealed umbilical stoma has been described previously and includes a posterior umbilical flap for improved cosmesis and stenosis prevention. We assessed long-term stomal stenosis. MATERIALS AND METHODS: We reviewed retrospectively the charts of 46 patients (mean age at surgery 14 years) of whom 35 had undergone concealed umbilical stoma creation and 11 the Malone antegrade continence enema procedure for continent urinary diversion. Urinary stomas were created from appendix in 20 cases, ileum in 8, sigmoid colon in 5, bladder in 1 and stomach in 1. Malone antegrade continence enema stomas were constructed from appendix in 10 cases and sigmoid colon in 1. A total of 21 patients underwent urinary diversion and augmentation cystoplasty. RESULTS: At followup of 12 to 84 months (median 3.4 years) 93.5% of patients had an intact stoma with no need for surgical revision. Of the remaining patients 3 (6.5%) required revision of the stoma at skin level for stomal stenosis at 1, 4 and 38 months after initial surgery and 2 had a brief period of indwelling catheterization for correction of stenosis. CONCLUSIONS: The concealed umbilical stoma technique provides an excellent cosmetic result with a low rate of stomal stenosis in patients requiring intermittent bladder or bowel catheterization.

Combined effect of terazosin and finasteride on apoptosis, cell proliferation, and transforming growth factor-beta expression in benign prostatic hyperplasia.

BACKGROUND: Medical treatment of benign prostatic hyperplasia (BPH) targets relief of symptoms by causing either relaxation of the prostatic smooth muscle with alpha1 adrenergic blockade, or shrinkage of the gland with 5alpha-reductase inhibitors. We recently demonstrated that alpha1-blockers, such as terazosin, induce apoptosis in prostatic cells. In this study, we examined the combined effect of finasteride and terazosin on the rate of apoptosis and cellular proliferation to investigate their potential synergy at the cellular level. METHODS: Prostate specimens were obtained from men who were treated with either finasteride (n = 24), terazosin (n = 42), or combination therapy (n = 10) for varying time periods (1 week to 36 months) for the relief of the symptoms of BPH. The proliferative and apoptotic indices of both stromal and epithelial prostatic cell populations were determined. Antibodies against TGF-beta1 and TbetaRII were used to examine the immunoreactivity of TGF-beta1 and TbetaRII, respectively, in all prostate tissue sections. RESULTS: The apoptotic index in both prostate cell populations was significantly higher following the combination treatment compared to terazosin or finasteride alone. There were no significant changes in the rate of cellular proliferation with any treatment. Furthermore, there was a significant increase in TGF-beta1 expression in the prostates of patients treated with terazosin or combination therapy, while there was no change in TbetaRII expression. CONCLUSIONS: These results support the concept that induction of prostate apoptosis is a potential molecular mechanism underlying the combination effect of alpha1 blockade with 5alpha-reductase inhibitors in the effective treatment of BPH. The upregulation of TGF-beta1 implies a role for this ligand as an effector of apoptosis induction in response to alpha1-blockade or finasteride therapy of BPH patients.

Bilateral nephrectomy with concomitant renal graft transplantation for autosomal dominant polycystic kidney disease.

PURPOSE: There has been controversy about pre-transplant nephrectomy in patients with autosomal dominant polycystic kidney disease. Kidneys may be removed in these patients when they cause respiratory compromise, early satiety, increased abdominal girth, pain, hematuria or recurrent infection. We determined whether concomitant bilateral nephrectomy at renal transplantation is safe and efficacious. MATERIALS AND METHODS: Between December 1996 and January 1999, 10 patients with autosomal dominant polycystic kidney disease underwent bilateral nephrectomy with concomitant renal grafting (group 1). We compared these patients to 9 with autosomal dominant polycystic kidney disease matched for age and gender who underwent transplantation only (group 2) and 4 with the same condition who underwent bilateral nephrectomy and renal transplantation as staged procedures (group 3). RESULTS: No patients died perioperatively. There was a lower rate of complications in group 1 than in groups 2 or 3. The only significant differences in intraoperative and perioperative parameters were operative time and intraoperative blood loss, which were greater in group 1 than in group 2. We noted no significant differences in groups 1 and 3. Patient satisfaction analyzed by a survey revealed that the 70% of group 1 patients who responded were satisfied with kidney removal and 7 of the 9 in group 2 desired native kidney removal. All group 3 patients already had a functioning renal graft but were satisfied with native kidney removal, although they would rather have undergone bilateral nephrectomy at transplantation. CONCLUSIONS: Our data imply that there is no higher morbidity or mortality when performing concomitant bilateral nephrectomy at renal transplantation in patients with renal failure due to autosomal dominant polycystic kidney disease. There was a higher rate of satisfaction in patients who underwent nephrectomy and transplantation simultaneously, while those who did not undergo concomitant procedures strongly desired to have had that option. Bilateral nephrectomy may alleviate symptoms while providing greater room for renal graft placement. When done without transplantation, bilateral nephrectomy resulted in the highest number of complications. Our data indicate that if bilateral nephrectomy is performed as an adjunct to transplantation, it should be done at renal grafting.