Ahmad Shabsigh

Rapid reduction in blood flow to the rat ventral prostate gland after castration: Preliminary evidence that androgens influence prostate size by regulating blood flow to the prostate gland and prostatic endothelial cell survival

Androgenic steroids regulate the development and size of the mammalian prostate gland. The mechanism(s) for this growth control might involve a direct effect on prostate cell proliferation and survival as well as more complex effects on the tissue environment supporting nourishment and oxygenation. In this study, we evaluated an animal model of androgen action on the prostate, the rat ventral prostate gland, to determine whether acute androgen withdrawal, by means of castration, might alter the primary blood flow to the prostate gland and for the effects of castration on prostatic endothelial cell viability.

Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis

OBJECTIVES Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. METHODS Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 10(7) LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. RESULTS Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P<0.0001) but no change in the number of BrdU positive cells. CONCLUSIONS This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

Erectile dysfunction is a marker for cardiovascular complications and psychological functioning in men with hypertension.

The aim of this study was to investigate the incidence of cardiovascular complications in hypertensive patients with erectile dysfunction (ED). An anonymous questionnaire was mailed to 467 and received from 104 hypertensive male patients. Despite the low response rate of 22%, the following interesting findings could be observed: 70.6% of the patients who responded suffered from ED. The hypertensive patients with ED had significantly higher prevalence of cardiovascular complications (P<0.05). The correlation between depression and low quality of life as well as between ED and low sexual satisfaction was also statistically significant (P=0.05). ED in hypertensive patients can be considered as a marker for cardiovascular complications in this patient group.

Preventing reservoir calculi after augmentation cystoplasty and continent urinary diversion: the influence of an irrigation protocol

One of the problems associated with bowel reservoirs is the development of calculi. The authors from New York describe their use of an irrigation protocol in 91 patients who had either an augmentation cystoplasty or continent urinary diversion. In addition to finding that patients with an abdominal stoma had a much higher chance of developing reservoir calculi, they found that using a definitive postoperative irrigation programme considerably reduced the incidence of calculi.

Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer.

PURPOSE We investigate the potential use of the phytotherapeutic PC-SPES to treat human prostate cancer, and evaluate its in vivo and in vitro activity, and clinical efficacy. MATERIALS AND METHODS PC-SPES was evaluated for its ability to induce apoptosis on prostate cancer cell lines LNCaP, PC3 and DU145. The effect of oral PC-SPES on growth of PC3 tumors present in male immunodeficient mice was studied. A total of 30 male nude mice were divided in 5 groups. In groups 1 control and 2 full dose therapy was started the same day of the tumor injection. In groups 3 control, 4 half dose and 5 full dose PC-SPES therapy was initiated 1 week after tumor injection. A total of 69 patients with prostate cancer were treated with 3 capsules of 320 mg. PC-SPES daily. Serum prostate specific antigen (PSA) responses and side effects were evaluated. RESULTS All of the cultured prostate cancer cell lines had a significant dose dependent induction of apoptosis following exposure to an alcoholic PC-SPES extract. Immunodeficient mice xenografted with the PC3 cell line had reduced tumor volume compared with sham treated controls when they were treated with a PC-SPES extract from the time of tumor cell implantation (931 +/- 89 versus 1,424 +/- 685 mm.3, p not significant) but not when the treatment was begun 1 week after tumor cell implantation. The testis, prostate, bladder and seminal vesicles of the treated mice were significantly reduced in weight compared with the sham treated animals. Of the patients with prostate cancer 82% had decreased serum PSA 2 months, 78% 6 months and 88% 12 months after treatment with PC-SPES. Side effects in the treated patient population included nipple tenderness in 42% and phlebitis requiring heparinization in 2%. CONCLUSIONS An extract of the phytotherapeutic agent PC-SPES proved to be active in inducing apoptosis of hormone sensitive and insensitive prostate cancer cells in vitro, and in suppressing the growth rate of a hormone insensitive prostate cancer cell line in vivo. The overwhelming majority of patients with prostate cancer treated with the agent experienced a decrease in serum PSA but also demonstrated a side effect profile comparable to estrogen treatment.

Sexual Function Following Bowel Vaginoplasty

PURPOSE We review our 23-year experience with bowel vaginoplasty, with particular attention to postoperative quality of life and sexual function. MATERIALS AND METHODS We reviewed the records of 57 patients who underwent bowel replacement vaginoplasty between 1980 and 2004. A total of 42 patients had the Mayer-Rokitansky syndrome, of whom 6 had varying forms of intersexuality, 6 had undergone surgery for pelvic malignancy, 1 had aphallia, 1 had cloacal exstrophy and 1 was the survivor of a conjoined twin separation. Replacement vaginoplasty was done using sigmoid colon in 39 patients, ileum in 9 and cecum in 9. Followup ranged from 18 months to 24 years, with a mean of 8.8 years. Outcome was evaluated by retrospective chart review, and the FSDQ, a validated, IRB approved instrument, was used to evaluate postoperative sexual function. RESULTS Among the 57 patients postoperative sexual function was evaluated in 44, 9 were lost to followup and 4 were considered too young for evaluation. Of the 44 patients 36 responded to the FSDQ, 6 refused and 2 were unable to complete the questionnaire adequately. Of the 36 patients who responded 15 were married and 31 were sexually active. On a scale of 0 to 5, 28 patients (78%) reported sexual desire, 33% sexual arousal, 33% sexual confidence and 28 (78%) sexual satisfaction. In addition, 20 patients (56%) reported frequent orgasms, 8 (22%) occasional orgasms and 8 (22%) no orgasms. A total of 32 patients (89%) reported adequate lubrication for intercourse and 2 reported dyspareunia. Two of the 36 patients performed home dilation and required estrogen suppositories. A total of 34 patients used home douching and 20 required pads for mucus production. CONCLUSIONS It appears that isolated bowel segments provided excellent tissue for vaginal replacement. For technical reasons we believe that colonic segments, particularly sigmoid, are preferable to small bowel. Sexual function following bowel vaginoplasty appears to be adequate and durable.

Cryoablation for clinically localized prostate cancer using an argon‐based system: complication rates and biochemical recurrence

Objective To determine the complication rates and biochemical recurrence after cryoablation of the prostate, using an argon gas‐based system, in patients with localized prostate cancer.

The effects of androgen deprivation on the prostate gland: cell death mediated by vascular regression.

Androgenic steroids are required to maintain the prostate gland in the adult state. Consistent with this requirement, androgen deprivation therapies typically induce a drastic regression of mature prostate tissue that is accompanied by the extensive loss of prostate cells through the programmed cell death process referred to as apoptosis. Whereas, in the past, the loss of prostate cells associated with androgen deprivation has generally been perceived to be a direct response of the androgen receptor-expressing prostate cells to an androgen-depleted environment, more recent studies of the prostate regression process suggest that it might instead be initiated by an indirect response of the prostatic parenchyma to an ischemic/hypoxic environment caused by a drastic reduction of blood flow to the tissue that occurs when androgens are withdrawn. This article reviews evidence that the prostatic vascular system is a primary target of androgen action and other evidence suggesting that the regression of the prostate parenchyma occurs secondarily to the regression of the prostate vascular system through cell death mediated by tissue ischemia/hypoxia.

Prostatic neoplasia in transgenic mice with prostate‐directed overexpression of the c‐myc oncoprotein

Promoter elements within the 5′ DNA region of the rat C(3)1 gene have been shown to direct prostate‐specific expression of gene products when they are fused through recombinant DNA procedures and used to produce transgenic mice. In order to test the in vivo effects of chronic overexpression of the mouse c‐myc protooncogene on the prostate glands of transgenic mice, we created several lines of C(3)1‐c‐myc transgenic mice and then examined the phenotype of males with this genetic alteration.

Regulation of Apoptosis in the Prostate Gland by Androgenic Steroids.

The prostate gland requires androgenic steroids for its appropriate embryological formation and postpubertal growth and, once at adult size, remains dependent on a continuous supply of androgens for its vitality and function. A reduction of the levels of circulating androgens will rapidly induce apoptosis of the cells of the prostate, leading to extensive glandular regression. Studies of rodent models of prostate response to castration have shown that there are some remarkable changes in the gene activity of prostate epithelial cells leading up to apoptosis. There is now evidence for a critical cell signaling pathway, regulated by c-fos expression, necessary for castration-induced apoptosis, as well as evidence that this signaling initiates an abrupt and transient alteration in the synthesis of fas antigen, p53, bax and bcl-2 proteins in the androgen receptor-expressing prostate epithelial cells, the cellular compartment that appears to be the most affected by castration. However, more recent studies suggest that these castration-induced effects on the prostate epithelial cells might be, at least in part, an indirect response to a critical reduction in blood flow to the prostate gland that precedes the onset of epithelial cell apoptosis. The castration effects on blood flow to the prostate gland seem to be related to vascular degeneration associated with apoptosis of a subset of prostate endothelial cells.