The purpose of this study was to determine the role of cyclooxygenase-2 (COX-2) and its metabolites in lower urinary tract function after induction of acute (4 h), intermediate (48 h), or chronic (10 day) cyclophosphamide (CYP)-induced cystitis. Bladders were harvested from euthanized female rats for analyses. Conscious cystometry was used to assess the effects of a COX-2-specific inhibitor, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl2(5H)-furanone (DFU, 5 mg/kg sc), a disubstituted furanone, in CYP-induced cystitis. COX-2 mRNA was increased in inflamed bladders after acute (12-fold) and chronic (9-fold) treatment. COX-2 protein expression in inflamed bladders paralleled COX-2 mRNA expression. Prostaglandin D2-methoxime expression in the bladder was significantly (P < or = 0.01) increased in acute (3-fold) and chronic (5.5-fold) cystitis. Prostaglandin E2 was significantly (P < or = 0.01) increased (2-fold) in the bladder with intermediate (1.7-fold) and chronic (2.6-fold) cystitis. COX-2-immunoreactive cell profiles were distributed throughout the inflamed bladder and coexpressed histamine immunoreactivity. Conscious cystometry in rats treated with CYP + DFU showed increased micturition intervals 4 and 48 h after CYP treatment and decreased intravesical pressures during filling and micturition compared with rats treated with CYP + vehicle. These studies suggest an involvement of urinary bladder COX-2 and its metabolites in altered micturition reflexes with CYP-induced cystitis.

Examined for more than a century, the potential for using injectables for prostatic tissue ablation remains significant. More systematic laboratory research and clinical trials, currently ongoing, need to be completed.

OBJECTIVES To evaluate the location and extent of diffusion that occurs when liquid is injected transurethrally into the prostate gland, by correlating real‐time fluoroscopy and gross pathology, and to quantify the variables that influence intraprostatic diffusion during chemoablation of the prostate. MATERIALS AND METHODS A solution of diatrizoate meglumine (HypaqueTM, Nycomed, Princeton, NJ) gentamicin and methylene‐blue dye (HGM) was injected transurethrally into the prostate in six dogs, using a passive‐deflection needle injection system. The intraprostatic diffusion characteristics were evaluated during each injection using real‐time C‐arm fluoroscopy, and following each injection by gross examination of methylene blue staining within the prostatic tissues. HGM back‐flow into the urethra at the time of injection was assessed by measuring gentamicin levels in the collected bladder irrigant after each injection, using a standard dilution formula. RESULTS There was variability in the intraprostatic diffusion both fluoroscopically and grossly. The needle occasionally assumed a straighter trajectory than its intended curve. Intraprostatic diffusion was detected in 12 of 36 injections (33%). Using standard manipulations of various devices increased the intraprostatic diffusion in these injections to almost 80%. There was less intraprostatic diffusion when the injection resistance was either extremely high or absent. There was no extraprostatic extravasation of HGM beyond the prostatic capsule. CONCLUSION Current methods of transurethral intraprostatic injection are variable for both the diffusion of HGM solution and in needle deployment. The gross diffusion patterns with the HGM solution were consistent with the diffusion patterns documented in our previous research using absolute ethanol. These and other factors may partly explain the variability of the lesions produced with ethanol injection. Therefore, more research is needed to further elucidate the diffusion characteristics of solutions injected intraprostatically using the transurethral approach.

BACKGROUND: Effective treatment of prostate cancer (PCa) remains a major challenge due to chemoresistance to drugs including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Ethanol and ethanol extracts are known apoptosis inducers. However, cytotoxic effects of ethanol on PCa cells are unclear. METHODS: In this study we utilized PC3 and LNCaP cell culture models. We used immunohistochemical analysis, western blot analysis, reactive oxygen species (ROS) measurement, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) Cell Proliferation Assay, Annexin-V staining and flow cytometry for quantification of apoptosis. In vitro soft agar colony formation and Boyden chamber invasion assays were used. Tumorigenicity was measured in a xenotransplantation mouse model. RESULTS: Here, we demonstrate that ethanol enhances the apoptosis-inducing potential of TRAIL in androgen-resistant PC3 cells and sensitizes TRAIL-resistant, androgen sensitive LNCaP cells to apoptosis through caspase activation, and a complete cleavage of poly (ADP)-ribose polymerase, which was in association with increased production of ROS. The cytotoxicity of ethanol was suppressed by an antioxidant N-acetyl cystein pretreatment. Furthermore, ethanol in combination with TRAIL increased the expression of cyclin-dependent kinase inhibitor p21 and decreased the levels of Bcl-2 and phosphorylated-AKT. These molecular changes were accompanied by decreased proliferation, anchorage-independent growth and invasive potential of PC3 and LNCaP cells. In vivo studies using a xenotransplantation mouse model with PC3 cells demonstrated significantly increased apoptosis in tumors treated with ethanol and TRAIL in combination. CONCLUSIONS: Taken together, use of ethanol in combination with TRAIL may be an effective strategy to augment sensitivity to TRAIL-induced apoptosis in PCa cells.

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