Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: an orthotopic in vivo model.

INTRODUCTION: The effects of a conditionally replicating adenovirus on various bladder cancer lines were explored, a truncated bone sialoprotein (BSP) promoter controlling the E1a/b lytic-regulating sequence was used, since BSP protein is found in many osteotropic neoplasms, including bladder cancer. METHODS: Reverse transcriptase polymerase chain reaction analysis was used to determine expression patterns of BSP and Coxsackie adenovirus receptor, a receptor known to interact with adenovirus, on multiple lines of bladder cancer (253J, 253J B-V, RT4, transitional cell carcinoma, T24, UMUC3, and WH). Ad-BSP-E1a was tested in vitro for lytic activity on 4 of these cell lines. The 253J B-V cell line was used and inoculated into female nude mice either subcutaneously in the flank or orthotopically into the bladder, and treated with control or Ad-BSP-E1a virus. RESULTS: BSP is expressed in RT4, transitional cell carcinoma, and WH. Meanwhile, Coxsackie adenovirus receptor was expressed in all lines except T24. Ad-BSP-E1a had the most impact on 253J and 253J B-V cells; cell density declined significantly when compared to phosphate-buffered saline and Ad-BSP-TK "dummy" virus-treatment groups. The 253J B-V tumors treated with Ad-BSP-E1a revealed a decreased percent change of size in the subcutaneous model when compared to controls at week 3. The orthotopic murine model showed decreased end tumor mass in the Ad-BSP-E1a treated group over controls. Histologic examination of in vivo tumors showed evidence of fibrosis and apoptosis in the Ad-BSP-E1a treated groups using hematoxylin-eosin, trichrome, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Control groups only had viable tumor in in vivo models. CONCLUSION: Adenovirus therapy of orthotopic murine bladder tumors is feasible. Ad-BSP-E1a is effective in treating very aggressive yet sensitive bladder tumor cells. Further study of this conditionally replicating adenovirus treatment (Ad-BSP-E1a) with chemotherapeutic combination is warranted, and future translation of such combination therapy into human beings is a possibility.

Voiding dynamics in women: a comparison of pressure-flow studies between asymptomatic and incontinent women.

OBJECTIVES: To define the normative values for pressure-flow studies in asymptomatic women and to compare them with the values in women with stress incontinence. METHODS: Asymptomatic women between the ages of 30 and 70 years were recruited from the community to undergo urodynamic studies (UDSs). Only women with no or minimal symptoms on the Urogenital Distress Inventory Questionnaire, minimal pelvic organ prolapse, and no previous surgery for incontinence were included. The results of the pressure-flow studies were compared with the values from women evaluated for stress urinary incontinence (SUI) between December 1998 and August 2000. RESULTS: Twenty asymptomatic women (mean age 41.7 years) met the inclusion criteria of the 59 who applied. Their pressure-flow data were compared with that of 40 women with symptoms of pure SUI selected from the 415 who underwent UDSs during this period, 16 of whom were found to have SUI during the UDS. The average maximal flow was 17.2 +/- 6.7 mL/s in the control population and 22.0 +/- 6.8 mL/s among women with genuine SUI during the UDS (P = 0.039). The detrusor pressure at the maximal flow averaged 24 +/- 10 cm H(2)O and 16.0 +/- 8.6 cm H(2)O for the control and SUI groups, respectively (P = 0.016). The voided volumes were somewhat higher for the SUI group (330 versus 419 mL, P = 0.041). CONCLUSIONS: These findings confirm the normative pressure-flow data in women and suggest that women with stress incontinence void at a lower detrusor pressure. A chronically reduced outlet resistance during bladder filling, which likely contributes to SUI, also appears to affect the voiding phase in stress-incontinent women.

Effect of 6F urethral catheterization on urinary flow rates during repeated pressure-flow studies in healthy female volunteers.

OBJECTIVES: To prospectively examine the effect of a 6F urethral catheter on the urinary flow rate in healthy women without lower urinary tract symptoms undergoing pressure-flow studies. METHODS: Women between the ages of 30 and 70 years, without lower urinary tract complaints and without a history of surgery for incontinence, were recruited. All women completed the Urogenital Distress Inventory-6 questionnaire, and only women with mild or no symptoms were enrolled. After a free flow rate was determined, cystometry and pressure-flow studies were performed once and then repeated using a 6F urethral catheter. The peak flow rates during the first and second studies were compared with one another and with the nonintubated values. RESULTS: Of the 59 women that applied, 20 volunteers (mean age 41.7 years) met the entry criteria and were evaluated. The mean nonintubated flow rate was 22.65 mL/s. With a 6F urethral catheter in place, our cohort had a mean peak flow rate of 16.25 mL/s on the first study and 15.25 mL/s on the second. A significant difference was demonstrated between the free and intubated peak flow rates for both the first (P = 0.0006) and the second (P = 0.0001) study. No significant difference was detected between the two intubated peak flow rates (P = 0.262). CONCLUSIONS: Our data suggest that the presence of a 6F urethral catheter significantly reduces the maximal flow rate compared with free flow studies. Whether these findings represent a truly obstructive effect of the catheter, detrusor fatigue, or other possible effect of the catheter remains to be elucidated.