Biomedical subjects

Osamu Ukimura

Publications and source records attributed to Osamu Ukimura.

At least 37 records · Page 2Linked to original sources

PubMed2004

Neuroselective current perception threshold evaluation of bladder mucosal sensory function.

OBJECTIVE: To evaluate human bladder mucosal sensory function by neuroselective Current Perception Threshold (CPT) measures from healthy and neuropathic bladders. METHODS: Eight healthy volunteers and 38 patients with urinary symptoms underwent conventional urodynamic tests including water-filling cystometry and ice water test. Standardized neuroselective CPT measures were obtained from the left index finger and the mucosa of the posterior bladder wall. Three different CPTs were obtained from each test site using a constant alternating current sinusoid waveform electrical stimulus presented at 2000Hz, 250Hz and 5Hz stimulation frequencies, which could selectively reflect the functions of the large myelinated fibers (A-beta-fiber), the small myelinated fibers (A-delta-fiber), and the unmyelinated fibers (C-fiber), respectively. RESULTS: As the determination of CPT values on the finger skin, the CPT values in the bladder could be determined using the neuroselective measures in all patients but three who had no sensory response (absence of sensation) caused by complete spinal injury. In the 8 patients with detrusor hyperreflexia due to incomplete spinal cord injury (supra-sacral lesion), the bladder CPT value (4.0+/-1.9) at 5Hz was significantly lower (p<0.01) than that in the controls (26.2+/-17.7). In the neurogenic bladders determined to be underactive (n=11, including post pelvic surgery, post infra-sacral level spinal cord injury and diabetes patients), the higher CPT values of bladder mucosal sensory functions were found at 5Hz (p<0.05), 250Hz (p=0.07), and 2000Hz (p<0.05) compared to the controls. CONCLUSIONS: Quantitative neuroselective measurement of CPT values in the human bladder mucosal function was feasible. Hypersensitivity or hyposensitivity of the urinary sensory function could be determined using the CPT values in comparison to control. The quantitative neuroselective estimation of the bladder sensory functions in different types of sensory peripheral nerve fibers may contribute to the appropriate selection of therapeutic strategy in patients with urinary sensory dysfunction.

Adult↗

PubMed2004

Can complexed prostate specific antigen enhance prostate cancer detection in Japanese men?

BACKGROUND: The aim of this study is to ascertain whether Bayer complexed PSA (cPSA) and volume referenced cPSA could enhance the detection of prostate cancer in Japanese men. METHODS: A total of 214 Japanese men whose serum total PSA (tPSA) values ranged from 1.2 ng/ml to 4600 ng/ml were enrolled from two institutions. Serum samples for tPSA, free PSA, PSA-alpha-1-antichymotripsin (PSA-ACT) and cPSA (ADVIA-Centaur) were obtained in all cases. In addition, total gland (TGV) as well as transition zone volume (TZV) were determined in all cases who underwent untrasound guided prostate biopsy (sextant and two additional transition zone biopsies). Biopsy outcome was correlated to the following parameters: tPSA, cPSA, PSA-ACT, free to total (F/T) PSA ratio, 2 complex to total (C/T) PSA ratios and 6 volume referenced parameters. RESULTS: Prostate cancer was detected in 85 of 214 patients (40%). The area under the receiver operating characteristic curve in non-volume referenced variables was highest for cPSA (0.736), followed by PSA-ACT (0.735), tPSA (0.722), F/T PSA ratio (0.613) and C/T PSA ratio (0.591). Comparing tPSA with the cutoff value of 4.0 ng/ml, the cutoff value with a 2.8 ng/ml of cPSA detected one more positive biopsy patient, decreasing one more cancer missed case and 8 more false positive cases. At sensitivities of 85% to 95% in men with tPSA between 4.00 and 10.00 ng/ml (n = 116), there were no significant differences in the corresponding specificities between tPSA and cPSA, or between cPSA and PSA-ACT. At sensitivities of 90% to 95%, the corresponding specificities of PSA-ACT adjusted for transition zone volume revealed best performance. As for the performance in men with a tPSA less than 4.0 ng/ml, the specificities of cPSA performed best, and differed significantly from PSA-ACT and F/T PSA at sensitivities of 80% to 90%. CONCLUSION: Bayer cPSA could replace the first screening test by total PSA and can enhance cancer detection, compared with PSA-ACT. However, cPSA did not provide additional value in differentiating cancer from non-cancer cases in men with a tPSA between 4.00 and 10.00 ng/ml.

Aged↗

PubMed2004

Possible contribution of prostatic anterior fibromuscular stroma to age-related urinary disturbance in reference to pressure-flow study.

Recently, we reported that the anterior fibromuscular stroma (AFMS) of the prostate has significant different innervation compared with the other glandular regions of the prostate. In healthy volunteers (n = 12) using transrectal ultrasound (US), or TRUS, monitoring during voiding, we observed dynamic change (p < 0.0001) of the thickness of the AFMS during voiding. The aim of this study was to reveal the possible functional contribution of the AFMS to micturition, as well as the age-related voiding dysfunction. In the patients (n = 56) with voiding dysfunction who underwent both pressure-flow study (PFS) for determining obstruction and TRUS monitoring during voiding, we measured the ultrasonic dynamic change of the lower urinary tract during voiding. In old men with voiding dysfunction, ultrasonic measurements of dynamic change in the AFMS (p < 0.01) as well as the opening urethra (p < 0.05) could contribute to diagnosing of the anatomical localization of obstructive lesions. The poor movement of AFMS could account for the age-related urinary disturbance in the patients without benign prostatic enlargement and without bladder neck obstruction.

Aged↗

PubMed2004

Hand-assisted retroperitoneoscopic radical nephrectomy and nephroureterectomy.

In laparoscopic operations for renal tumor and upper urinary-tract transitional-cell carcinoma (TCC), three approaches - the transperitoneal, retroperitoneal, and transperitoneal hand-assisted - have been reported. We have performed hand-assisted retroperitoneoscopic radical nephrectomy (RN) since 1999 and nephroureterectomy (NU) since 2000. The surgical techniques and the operative results of 95 cases of RN and 54 cases of NU are described and analyzed. These procedures were effective and safe for renal tumors and upper urinary-tract TCC.

Carcinoma, Transitional Cell↗

PubMed2004

Real-time transrectal ultrasonography during laparoscopic radical prostatectomy.

PURPOSE: We describe the technical aspects of real-time transrectal ultrasound (TRUS) monitoring and guidance during laparoscopic radical prostatectomy (LRP). Furthermore, we describe the TRUS visualized anatomy of periprostatic structures during LRP. MATERIALS AND METHODS: In 25 consecutive patients undergoing transperitoneal LRP, baseline preoperative, real-time intraoperative and immediate postoperative TRUS evaluations were performed. To define periprostatic anatomy precisely TRUS measurements were obtained with specific reference to the neurovascular bundle (NVB), prostate apex, membranous urethra, bladder neck, rectal wall and any cancer nodule. Conventional gray scale, power Doppler, harmonic imaging and 3-dimensional ultrasound functions were used. RESULTS: Real-time TRUS navigation facilitated 3 technical aspects of LRP. 1) It identified the correct plane between the posterior bladder neck and prostate base, allowing quick laparoscopic identification of the vasa and seminal vesicles. 2) It identified the occasional, difficult to see distal protrusion of the prostate apex posterior to the membranous urethra, thus enhancing apical dissection with negative margins. 3) It provided visualization of any hypoechoic nodule abutting the prostate capsule, alerting the laparoscopic surgeon to perform wide dissection at that location. TRUS measured various anatomical parameters including i) the mean distance +/-SD between the NVB and the lateral edge of the prostate a) at apex (1.9 +/- 0.9 mm), b) base (2.5 +/- 0.8 mm) and c) tip of seminal vesicle (4.0 +/- 1.6 mm), ii) the dimensions of the NVB a) before (4.5 x 3.9 mm), b) after (4.2 x 3.6 mm) nerve sparing LRP and c) after nonnerve sparing LRP (0.9 x 0.9 mm), iii) arterial blood flow resistive index within NVB a) before (0.83 +/- 0.04), b) after (0.84 +/- 0.03) nerve sparing LRP and c) after nonnerve sparing LRP (0), iv) and the length of membranous urethra a) before (12.2 +/- 1.1 mm) and b) after (11.7 +/- 1.0 mm) surgery. Focal distortion of the prostate surface by an exophytic nodule was visualized on TRUS in 3 patients, necessitating ipsilateral nerve resection at LRP and contributing to negative surgical margins. CONCLUSIONS: This initial experience suggests that real-time intraoperative TRUS guidance may enhance anatomical performance of LRP. This improved understanding of periprostatic anatomy has the potential to improve functional and oncological outcomes. Such corroboration is awaited.

Humans↗

PubMed2004

Retroperitoneoscopic heminephroureterectomy for children with duplex anomaly: Initial experience.

OBJECTIVES: To evaluate the feasibility of retroperitoneoscopic heminephroureterectomy for children with duplex anomaly. METHODS: Retroperitoneoscopic heminephroureterectomy was performed in five children (four girls and one boy) with complete duplication of the ureter, of whom four (age range 1-5 years; mean age 3.3 years) had upper pole ectopic megaureters and one (3 years old) had an upper pole megaureter with ureterocele. In the patient with ureterocele, distal ureterectomy and ureterocelectomy were performed by Pfannenstiel incision. RESULTS: The mean operation time was 346 min (range 270-450 min) in the four patients with ectopic megaureter and 420 min (330 min for heminephroureterectomy) in the patient with ureterocele. The mean estimated blood loss was 43 mL (range 5-100 mL) in the four patients with ectopic megaureter and 40 mL in the patient with ureterocele. No postoperative complications were observed. Postoperative intravenous pyelography showed normal pyelogram and renal function of the preserved lower pole in all cases. CONCLUSIONS: Retroperitoneoscopic heminephroureterectomy for children is feasible, safe and has good postoperative results, including cosmetic results. However, the operation time needs to be reduced.

Child, Preschool↗

PubMed2004

Effects of acupuncture for chronic pelvic pain syndrome with intrapelvic venous congestion: preliminary results.

BACKGROUND: The present study was designed to reveal the usefulness of acupuncture for chronic pelvic pain syndrome with intrapelvic venous congestion as evaluated by symptom scores, transrectal ultrasonography (TRUS) and magnetic resonance (MR) venography. METHODS: Ten male patients suffering from non-inflammatory chronic pelvic pain syndrome (NIH category IIIB) with intrapelvic venous congestion were treated using acupuncture. Eight patients had previously received pharmacotherapy, which was unsuccessful. Acupuncture was performed using disposable stainless steel needles, which were inserted into the bilateral BL-33 points and rotated manually for 10 min. The treatment was repeated every week for 5 weeks without other therapeutic maneuvers. Results from TRUS and MR venography, as well as clinical symptoms based on the NIH chronic prostatitis symptom index (NIH-CPSI) and the international prostate symptom score (IPSS), were compared before and after the treatment. RESULTS: No side-effects were recognized throughout the treatment period. The average pain and QOL scores of the NIH-CPSI 1 week after the 5th acupuncture treatment decreased significantly (P < 0.05 and P < 0.01, respectively) compared with the baseline. The maximum width of the sonolucent zone 1 week after the 5th treatment also decreased significantly (P < 0.01, compared with the baseline). Intrapelvic venous congestion demonstrated by MR venography was significantly improved in four patients. CONCLUSION: This study provided novel information concerning the therapeutic effects of acupuncture on non-inflammatory chronic pelvic pain syndrome.

Acupuncture Therapy↗

PubMed2004

Radio-frequency ablation of renal cell carcinoma in patients who were at significant risk.

OBJECTIVE: Although radio-frequency ablation (RFA) has been recently applied as a minimally invasive treatment option for renal cell carcinoma (RCC), indication of this modality remains a critical issue due to the lack of complete tumor destruction as well as the uncertainty of its long-term efficacy. We report the efficacy of RFA for nine carefully selected patients with RCC who had significant reason to avoid invasive surgical treatment under general anesthesia. METHODS: Radio-frequency ablation was performed under epidural or local anesthesia by ultrasound or computed tomography (CT) guidance in nine patients with biopsy proven RCC (mean diameter, 38 mm; range, 20-53 mm), who were at significant operative or anesthetic risk for invasive surgery. Follow-up enhanced CT scans or magnetic resonance images were evaluated every 3-6 months and an evaluation of metastasis was performed every 6 months. RESULTS: At a mean follow-up of 17 months, seven (78%) of the nine patients with renal tumor showed no tumor enhancement. The renal function of all patients was well preserved. All patients were able to continue undergoing their respective treatments for active diseases in other organs in parallel to the RFA treatment. No distant metastasis, urine leakage were reported and one case of temporary hematuria and one case of peri-renal hemorrhage not requiring blood transfusion were encountered. Intra-operative ultrasonography was useful in the real-time monitoring of the minimally excessive extension of ablation into the normal parenchyma. CONCLUSION: Radio-frequency ablation appears to be an effective and safe minimally invasive therapeutic option for selected patients with RCC who have reason to avoid invasive surgery under general anesthesia.

Aged↗

PubMed2003

Firing of micturition center neurons in the rat mesopontine tegmentum during urinary bladder contraction.

Micturition is controlled by a network of brainstem neurons involving the Barrington's nucleus. To depict clearly the brainstem system for micturition control, the present study was designed to record single neuronal activity in the mesopontine tegmentum including the Barrington's nucleus, and to observe its precise timing in relation to bladder contraction recorded simultaneously. About 1/5 of neurons encountered had firing modulated in relation to bladder contraction. Three types of neurons were distinguished; those which fired only prior to the start of contraction (type E1), those whose firing started shortly prior to and was maintained during contraction (type E2), and those whose firing was strongly suppressed during contraction (type I). Type E2 neurons were most frequently observed in the Barrington's nucleus and its close vicinity, while the neurons of the other two types were scattered widely in the mesopontine tegmentum. The results show clearly that direct neural signals to induce bladder contraction may arise from the Barrington's nucleus, and that the nucleus may receive regulatory inputs from wide areas of the mesopontine tegmentum. In addition, the present study clarified that the noradrenergic and cholinergic neurons, which are located in nuclei adjoining the Barrington's nucleus and function to control sleep/wakefulness, may not be concerned in controlling micturition directly.

Action Potentials↗

PubMed2003

Ultrasonic measurement of bladder weight as a novel urodynamic modality.

Although pressure-flow studies (PFS) are currently recognized as the gold standard for the diagnosis of infravesical obstruction, their clinical use is limited, due to the invasive nature of procedure. Recently, we developed a new urodynamic parameter, ultrasound estimated bladder weight (UEBW), which was calculated from the bladder wall thickness measured ultrasonically and intravesical volume. Our comparative study between UEBW and PFS showed that UEBW diagnosed infravesical obstruction with a diagnosis accuracy of 73% using a cut-off value of 35 gm. UEBW could also be used as a reliable tool in monitoring therapeutic effects on BPH patients in terms of the relief of obstruction. In addition, UEBW is of clinical use in the management of neurogenic bladder dysfunction, in which there was a significant negative correlation noted between UEBW and bladder compliance. Consequently, UEBW could be a reliable predictor for a low-compliant bladder. Since UEBW can be obtained non-invasively, it is readily applicable to pediatric urology. In healthy children, UEBW increased significantly with age. For the evaluation of UEBW in an individual child patient, the deviation from age-matched UEBW, obtained from the formula of the linear correlation between UEBW and age, was employed. In our recent studies, the deviation from age-matched UEBW is likely to be used as a predictor for bladder dysfunction in children, such as secondary vesicoureteral reflux and a low-compliant bladder. In conclusion, UEBW is promising as a non-invasive urodynamic modality capable of evaluating bladder hypertrophy with its functional abnormalities.

Humans↗

PubMed2003

Bladder capacity at the time of enuresis.

OBJECTIVES: To evaluate bladder capacity at the time of enuresis and compare the daytime capacity of enuretics with that of controls. METHODS: The functional bladder capacity (FBC), which was the maximal endurable capacity in the daytime, the ordinary bladder capacity (OBC), which was the capacity at ordinary urinary sensation in the daytime, and the enuretic bladder capacity (EBC), which was the capacity at the time of enuresis, were measured in 67 patients with monosymptomatic nocturnal enuresis. The EBC was measured using a diaper and enuresis alarm. The FBC, OBC, and nocturnal bladder capacity, which was the maximal voided volume in the nighttime, were also measured in 67 controls. RESULTS: The FBC was not significantly different between enuretics and controls. The EBC in enuretics was significantly smaller than the nocturnal bladder capacity in controls. In enuretics, the EBC was significantly smaller than the FBC and was similar to the OBC. In controls, no statistically significant differences were found between the FBC and the nocturnal bladder capacity. CONCLUSIONS: In enuretics, the bladder capacity during sleep was significantly smaller than the daytime functional capacity. In controls, on the other hand, the bladder capacity during sleep did not differ from the daytime functional capacity. Our understanding of the bladder capacity in enuretics may need to change in view of this result. The inability to hold urine during sleep may be an important cause of nocturnal enuresis.

Adolescent↗

PubMed2003

Isoliquiritigenin inhibits the growth of prostate cancer.

OBJECTIVE: Isoliquiritigenin, one of the components in the root of Glycyrrhiza glabra L., is a member of the flavonoids, which are known to have an anti-tumor activity in vitro and in vivo. In this study, we investigated the anti-tumor effect of isoliquiritigenin on prostate cancer in vitro. METHODS: DU145 and LNCaP prostate cancer cell lines were used as targets. We examined the effects of isoliquiritigenin on cell proliferation, cell cycle regulation and cell cycle-regulating gene expression. Further, we investigated the effects of isoliquiritigenin on the GADD153 mRNA and protein expression, and promoter activity. RESULTS: Isoliquiritigenin significantly inhibited the proliferation of prostate cancer cell lines in a dose-dependent and time-dependent manner. Fluorescence-activated cell sorting (FACS) analysis indicated that isoliquiritigenin induced S and G2/M phase arrest. Isoliquiritigenin enhanced the expression of GADD153 mRNA and protein associated with cell cycle arrest. Further, isoliquiritigenin stimulated transcriptional activity of GADD153 promoter dose-dependently. CONCLUSION: These findings suggest that isoliquiritigenin is a candidate agent for the treatment of prostate cancer and GADD153 may play an important role in isoliquiritigenin-induced cell cycle arrest and cell growth inhibition.

CCAAT-Enhancer-Binding Proteins↗

PubMed2003

Significant antitumor effect of intratumoral ethanol injection on renal cell carcinoma.

OBJECTIVE: The effects of intratumoral ethanol injection on renal cell carcinoma (RCC) heterotransplanted in nude rats were evaluated. MATERIALS AND METHODS: The OUR95AF human RCC cell line was inoculated subcutaneously into the backs of nude rats. Four weeks after transplantation, the size of tumors became 1.5-2.0 cm in maximal length, and 95% ethanol was injected intratumorally once a week for five weeks. The effectiveness of this treatment was evaluated by measurement of tumor volume, magnetic resonance (MR) imaging using Gadopentetate-diethylenetriaminepentaacetic acid (Gd-DTPA) and histological examinations. RESULTS: In the ethanol injected group, no increase in tumor volume was recognized. The growth of the tumors was significantly suppressed after the third injection. Non-enhanced parts in MR imaging were observed in the central region of the tumors at the second injection, and increased at the third injection. After the fifth injection, only small parts of non-enhanced regions remained. Degenerative necrosis was histologically found in the non-enhanced parts of the MR image. The signal to noise ratio (SNR) and the contrast to noise ratio (CNR) calculated from T1 weighted imaging using Gd-DTPA, and relative enhancement (RE) were thought to be good parameters for evaluating the effect of ethanol injections. CONCLUSION: Intratumoral ethanol injection was very effective against RCC. Five weekly injections of ethanol induced necrosis of the tumor. MR imaging using Gd-DTPA may be a useful method for evaluating the effect of ethanol injection.

Animals↗

PubMed2003

Laparoscopic correction of vesicoureteral reflux using the Lich-Gregoir technique: initial experience and technical aspects.

We report two female cases with vesicoureteral reflux (VUR) who underwent laparoscopic correction of VUR by the Lich-Gregoir technique. One patient was 10 years of age, with international grade III reflux of the left ureter; the other was 27 years of age, with grade II reflux of the right ureter. The respective operating times were 6 h 40 min and 6 h 10 min. There were no complications during surgery. Although post-surgical ultrasonography revealed mild hydronephrosis in the adult patient, the condition resolved spontaneously 2 months after surgery. The disappearance of reflux was confirmed in both cases by voiding cystography 6 months after surgery.

Adult↗

PubMed2003

Hand assisted retroperitoneoscopic nephroureterectomy: comparison with the open procedure.

PURPOSE: We report our initial experience with hand assisted retroperitoneoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma and compared our results to those of a contemporary series of open nephroureterectomy. MATERIALS AND METHODS: Clinical data on 34 consecutive patients who underwent hand assisted retroperitoneoscopic nephroureterectomy were reviewed and compared with those on 34 who underwent open nephroureterectomy. All specimens were extracted intact. RESULTS: Total operative time was similar in the 2 groups (233 versus 236 minutes). Estimated blood loss was significantly less in the hand assisted laparoscopy group (236 versus 427 ml.). During convalescence the frequency of parenteral analgesia postoperatively was significantly lower in the laparoscopy group than in the open surgery group. The former patients had a significantly shorter interval to oral intake and ambulation as well as a shorter hospital stay and convalescence compared with those who underwent open surgery. In each group the complication rate was 12% (4 of 34 cases). In the hand assisted laparoscopy group 1 conversion to an open procedure was due to bleeding. There was recurrence in 4 of the 34 patients (12%) in the laparoscopy group, including 2 with bladder recurrence and 2 with metastases, at an average followup of 13.1 months. CONCLUSIONS: Hand assisted retroperitoneoscopic nephroureterectomy is an effective and safe alternative to open nephroureterectomy for upper urinary tract transitional cell carcinoma.

Adult↗

PubMed2003

Prostate cancer detection using power Doppler imaging.

Various preliminary and reassessment articles focusing on power Doppler imaging to detect prostate cancer have studied the potential of this powerful tool. By identifying abnormal vascular flow, power Doppler imaging can enhance prostate cancer detection. However, according to recent articles, the applications for biopsy-guided power Doppler imaging targeting the intermediate serum prostate-specific antigen range has some limitations. Three-dimensional reconstruction of power Doppler imaging is a promising technique to improve cancer detection.

Biopsy↗

PubMed2003

Significant antitumoral activity of cationic multilamellar liposomes containing human IFN-beta gene against human renal cell carcinoma.

PURPOSE: Immunotherapy is the most effective treatment against metastatic renal cell carcinoma (RCC). However, the response rate is approximately 15%. More effective therapy is, therefore, needed for patients with metastatic RCC. We then examined the antitumor effect of cationic multilamellar liposome containing human IFN-beta (huIFN-beta) gene (IAB-1) against RCC. EXPERIMENTAL DESIGN: Concentrations of huIFN-beta protein were measured by ELISA. The cytotoxicity of IAB-1 against human RCC (NC65, ACHN, and freshly isolated RCC cells), prostate and bladder cancer cell lines, and renal proximal tubule endothelial cells (RPTEC5899) was examined by the colorimetric method using tetrazolium salt. Apoptosis was assessed by the acridine-orange staining. For in vivo study, we used NC65 cells inoculated into severe combined immunodeficiency mouse. RESULTS: The RCC cells treated with IAB-1 secreted significant amounts of huIFN-beta protein continuously. Drastic in vitro cytotoxic effect of IAB-1 against RCC was observed. In contrast, treatment with 1000 IU/ml recombinant huIFN-beta protein resulted in weak cytotoxicity. The cytotoxic effect against prostate and bladder cancer cell lines was less than that against RCC. Furthermore, no significant cytotoxicity was observed in RPTEC5899 cells. Apoptosis was observed in the cells treated with IAB-1, but recombinant huIFN-beta failed to induce apoptosis. The size of NC65 tumors transfected with IAB-1 in mice was significantly smaller than that receiving injection of empty liposome or recombinant huIFN-beta protein. CONCLUSION: These findings indicate that IAB-1 may have an antitumor activity against human RCC by inducing apoptosis, suggesting its potential clinical application for gene therapy against RCC.

Acridine Orange↗

PubMed2002

Synergistic cytotoxicity and apoptosis of JTE-522, a selective cyclooxygenase-2 inhibitor, and 5-fluorouracil against bladder cancer.

PURPOSE: Cyclooxygenase-2 (COX-2) is a key inducible enzyme involved in the production of prostaglandins that has been shown to induce apoptosis in various cancer cells. Several anticancer agents also mediate apoptosis and may share the common intracellular pathways leading to apoptosis. Since over expression of COX-2 has been demonstrated in bladder cancer, we reasoned that combination treatment with a COX-2 inhibitor and anticancer agents in bladder cancer cells may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 induces apoptosis in bladder cancer cells and whether JTE-522 may act synergistically with anticancer agents to achieve cytotoxicity and apoptosis in these cells. MATERIALS AND METHODS: Cytotoxicity was determined by microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. RESULTS: COX-2 mRNA expression was observed in the HT1197 bladder cancer cell line. JTE-522 was cytotoxic in HT1197 cells. Treating HT1197 cells with JTE-522 combined with doxorubicin or mitomycin C did not show synergistic cytotoxicity. However, combination treatment of HT1197 cells with JTE-522 and 5-fluorouracil (5-FU) resulted in a synergistic cytotoxic effect. Synergy was also achieved in the T24 bladder cancer line. Synergistic cytotoxicity was noted irrespective of treatment sequence but the highest percent cytotoxicity was obtained when HT1197 cells were treated with JTE-522 and 5-FU simultaneously. The synergy achieved in cytotoxicity with JTE-522 and 5-FU was shown to be due to apoptosis. The mechanisms responsible for synergistic cytotoxicity and apoptosis was examined. Treating HT1197 cells with 5-FU enhanced expression of the pro-apoptotic molecule Bax, while JTE-522 treatment reduced expression of the anti-apoptotic molecule Bcl-XL, resulting in a significantly higher ratio of Bax-to-Bcl-XL. CONCLUSIONS: This study shows that combination treatment of bladder cancer cells with the selective COX-2 inhibitor JTE-522 and 5-FU results in synergistic cytotoxicity and apoptosis due to the enhanced Bax-to-Bcl-XL expression ratio. These findings support the in vivo potential application of a combination of JTE-522 and 5-FU for bladder cancer.

Antimetabolites, Antineoplastic↗