It is well known that renal cell carcinoma shows poor responses upon chemotherapy, and a multidrug-resistance has been suggested as one of the possible mechanisms of their resistances to chemotherapeutics of renal cell carcinoma as well as other malignancies. In our previous study, MDR was expressed relatively high in A-498 cell line, low in Caki-2 cell line. From these observation A-498 was selected as the MDR positive cell line and Caki-2 as the MDR negative cell line and then a study was performed to evaluate the effect of verapamil and cyclosporin A on the cytotoxicity of vinblastine, which are known as the most effective chemotherapeutic agent on human renal cell carcinoma, upon these cell lines. And we tried to evaluate the effect of combination of verapamil and cyclosporin A on the cytotoxicity of vinblastine. Verapamil, in concentration of 0.1 uM, did not enhance the anticancer effect of vinblastine on A-498 cells but with the concentration of 1uM and 10uM, it decreased IC50 of vinblastine from 0.4 ug/ml when only vinblastine was used to 0.05 and 0.08, showing the dose modification effect of 8.40 and 5.25 respectively (p<0.05, by Mann Whitney test) Cyclosporin A, in all the concentration of 0.3, 1, 3uM, also decreased IC of vinblastine on A-498 cells to 0.08, 0.05, 0.08 ug/ml respectively, showing the dose modification effect of 5.25 to 8.40 (p<0.05, by Mann Whiney test). In caki-2 cells in which MDR1 and p-glycoprotein expression were barely detected, verapamil and cyclosporin A did not show any effect upon the cytotoxicity of vinblastine. Combination of 0.3uM of cyclosporin A and 0.1uM or 1uM of verapamil did not resistance modulating agents to enhance the cytotoxicity of vinblastine in renal cell carcinoma with enhanced multidrug resistance, but the combination of these drugs did not show any synergistic effect. And further studies including in vivo study and combination of cyclosporin A are needed before clinical trials to improve chemotherapeutic effect upon renal cell carcinoma.
Carcinoma, Renal Cell* ; Cell Line* ; Cyclosporine* ; Drug Resistance, Multiple ; Drug Therapy ; Humans* ; Inhibitory Concentration 50 ; P-Glycoprotein ; Verapamil* ; Vinblastine*

Purpose: To investigate the correlation between preoperative De Ritis ratio (aspartate transaminase [AST]/alanine transaminase [ALT]) and postoperative clinical outcome in patients with upper urinary tract carcinoma (UTUC) who underwent radical nephroureterectomy (RNU) and adjuvant chemotherapy (ACH). Materials and Methods: We respectively analyzed the clinical and pathological data of 102 patients who underwent RNU and ACH for UTUC. Patients were divided into 2 groups, according to the optimal value of AST/ALT ratio. The effect of the AST/ALT ratio was analyzed by the Kaplan-Meier method and Cox regression hazard models for patients’ cancer-specific survival (CSS) and overall survival (OS). Results: Mean survival time was 50.5±41.2 months. Mean age was 61.4±9.7years. Forty-one of the patients (46.5%) were in the high AST/ALT group. According to receiver operating characteristic analysis, the optimal AST/ALT ratio was 1.2. In Kaplan-Meier analyses, the high AST/ALT group showed worse outcomes in OS (p=0.007) and CSS (p=0.011). Using Cox regression models of clinical and pathological parameters to predict OS, high AST/ALT ratio (hazard ratio [HR], 5.428; 95% confidence interval [CI]; 1.803–16.334; p=0.002), pathological T3 (pT3) or higher (HR, 1.464; 95% CI; 1.156-1.857; p=0.002), and to predict CSS, high AST/ALT ratio (HR, 4.417; 95% CI; 1.545–12.632; p=0.005), and pT3 or higher (HR, 1.475; 95% CI; 1.172–1.904; p=0.002) were determined as independent prognostic factors. Conclusions Pretreatment AST/ALT ratio is a significant independent predictor of CSS and OS in advanced UTUC patients receiving systemic ACH after RNU.

PURPOSE: The role of apoptosis in the pathogenesis of ureteral damage from obstructive uropathy has rarely been studied. This study was performed to determine the protein expression of the apoptosis-associated genes in the pathogenesis of ureteral damage during the course of obstructive uropathy in ligated rat ureters. MATERIALS AND METHODS: After unilateral ligation of the ureter, each group of five Sprague-Dawley rats was sacrificed and examined at 1, 5, 10, 15, 20, 25, 30 and 35 days after ligation: five rats with normal ureters were also examined as controls. The protein expressions of the fas-associated death domain (FADD), Bax, Bcl-xL and cyclooxygenases (COX)-2 genes in obstructed ureters were assessed by performing Western blotting. RESULTS: The expressions of FADD protein in the 20 and 25 day-obstructed ureters (DOUs) were significantly higher than that in control ureters and the peak was reached in the 25 DOUs. The expressions of Bcl-xL protein in the 20, 25 and 30 DOUs were significantly higher than that in the control ureters and the peak was reached in the 25 DOUs. The expression of COX-2 protein in the 5, 10, 15, 25 DOUs were significantly higher than that in the control ureters and the peak was reached in the 10 DOUs. CONCLUSIONS: The FADD and Bcl-xL genes were involved in apoptosis of the obstructed ureter. The peaks of their expressions were at 25 DOUs. The expression of the COX-2 gene may be related with apoptosis in the obstructed ureter.
Animals ; Apoptosis ; bcl-X Protein ; Blotting, Western ; Ligation ; Prostaglandin-Endoperoxide Synthases ; Rats* ; Rats, Sprague-Dawley ; Ureter* ; Ureteral Obstruction

A study was performed to determine the prophylactic efficacy of intravesical BCG instillation in 82 patients with high risk superficial bladder tumors. Recurrent, grade III, multiple(more than 3) or large(more than 3cm) stage Ta orT1 tumors were included. They were treated with 6 weekly instillation of 120mg of BCG after transurethral resection. Another thirty six patients treated with transurethral resection alone were selected as a control group. All the patients were followed more than 24 months, with the mean of 32 months. The one year recurrence rate was 54% in BCG group and 74% in controls, which was statistically different(p<0.05, by Chi-square test), but two year recurrence rate was 71% in BCG group and 82% in controls, which was not statistically different (p>0.05). The median interval of recurrence from treatment was l4.5 months in the BCG group which was longer than that of 7 months in controls and the recurrence per l00 patient months was 7.86 and l4. 68(p<0.05), respectively. In 56 patients with recurrent tumors after BCG treatment, the tumor stage, grade, number and size of the recurrent tumors were lowered significantly compared to the initial tumors (p<0.05). One patient of the BCG group and 3 of the controls had recurrent tumors with progression to muscle invasion. In summary, BCG instillation improved stage and grade, decreased number and size of the recurrent tumors, and delayed the time of recurrence in patients with high risk superficial bladder tumors. Also the overall one year recurrence rate was significantly improved. but two year recurrence rate was not significantly improved.
Bacillus* ; Humans ; Mycobacterium bovis ; Recurrence ; Risk Factors ; Urinary Bladder Neoplasms* ; Urinary Bladder*

Small heterodimer partner (SHP) is an atypical member of nuclear receptor superfamily that lacks a DNA-binding domain. In previous study, we showed that SHP, c-jun, p65 of NF-kappaB subunits, and p21WAF1 expression was increased during monocytic differentiaton with the exposure of human leukemia cells to a differentiation agent, PMA. In this study, c-Jun and p65 were shown to mediate the transcriptional activation of the SHP promoter. In addition, SHP induced the cell cycle regulatory protein levels and cooperatively increased an induction of p21WAF1 expression with p65. Furthermore, SHP protected differentiated cells from etoposide-induced cellular apoptosis through the induction and cytoplasmic sequestration of p21WAF1. Complex formation between SHP and p21WAF1 was demonstrated by means of coimmunoprecipitation. These results suggest that SHP prolongs a cellular survival of differentiating monocytes through the transcriptional regulation of target genes of cell survival and differentiation.
*Apoptosis ; Cell Differentiation ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism ; Gene Expression Regulation ; Humans ; Monocytes/cytology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-jun/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism ; Transcription Factor RelA/genetics/metabolism

BACKGROUND: Calcium plays a key role in vascular contraction and regulates receptor sensitivity to certain neurotransmitters. Calcium channel blockers are useful in the treatment of both clinical and experimental hypertension. The present study was designed to examine whether there is an alteration of the activity of calcium channels in association with the development of hypertension. METHODS: Deoxycorticosterone acetate(DOCA)-salt hypertension was made by subcutaneous implantation of DOCA(200mg/kg)strip plus saline drinking(1%) and 2-kidney, 1 clip(2KIC)hypertension by clipping the left renal artery with a silver clip(internal gap of 0.2mm). They were used 4 weeks later. Age-matched normal rats served as a control. Mean arterial pressure(MAP) and heart rate(HR) were continuously recorded from the right femoral artery. The drugs were administered intravenously. RESULTS: Vehicle alone was without effect on MAP or HR. In normotensive rats, nifedipine infusion(5 and 10ug/kg/min)caused a dose-dependent decrease in MAP without significant changes in HR, while Bay k 8644(Bay K, 5 and 10 ug/kg/min) increased MAP transiently. Both the depressor response to nifedipine and the pressor response to Bay k were more marked in DOCA-salt hypetensive rats than in normotensive rats. The maximal changes in MAP indced by nifedipine(5 and 50 ug/kg) or Bay K(5 and 50 ug/kg) were also enhanced in 2KIC hypertensive rats as compared with control rats. CONCLUSION: These results indicate that calcium channel inhibitors and activators can affect on the regulation of blood pressure in an opposite fashion. It is also suggested that the activity of calcium channels might be altered in the developement of experimental hypertension.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester* ; Animals ; Bays* ; Blood Pressure ; Calcium ; Calcium Channel Blockers ; Calcium Channels ; Desoxycorticosterone ; Femoral Artery ; Heart ; Hypertension ; Neurotransmitter Agents ; Nifedipine* ; Rats* ; Renal Artery ; Silver

Purpose: To evaluate the clinical usefulness of the Seoul National University Prostate Cancer Risk Calculator (SNU-PCRC) to reduce unnecessary prostate biopsy and to increase the detection rate of high-risk cancer. Materials and Methods: We retrospectively analyzed 546 patients who underwent prostate biopsy between 2014 and 2016. The subjects were divided into 2 groups based on the type of risk calculator used: conventional and SNU-PCRC group. In the SNU-PCRC group, prostate biopsy was recommended when the probability of SNU-PCRC was more than 30%. Results: The SNU-PCRC group had significantly smaller prostate volume (p=0.010) and significantly more digital rectal examination and transrectal ultrasonography (TRUS) abnormalities (p=0.011 and p=0.010, respectively). Overall detection (71.9% vs. 32.1%) and high-risk cancer detection rates (40.6% vs. 19.3%) were significantly higher in the gray zone (prostate-specific antigen=4-10 ng/mL) (p<0.001 and p=0.006). The group with prostate cancer risk ≥30% on the SNU-PCRC compared to <30% group, overall detection rate of 72.3% versus 30.2% and high-risk detection rate of 60.6% versus 18.3% were significantly different (p<0.001 and p<0.001). Applying the SNU-PCRC to the conventional group could avoid unnecessary prostate biopsy in 50.6%. Conclusions SNU-PCRC is clinically useful to reduce unnecessary prostate biopsy and increase overall detection rate and high-risk cancer detection rate.

Purpose: To evaluate the clinical usefulness of the Seoul National University Prostate Cancer Risk Calculator (SNU-PCRC) to reduce unnecessary prostate biopsy and to increase the detection rate of high-risk cancer. Materials and Methods: We retrospectively analyzed 546 patients who underwent prostate biopsy between 2014 and 2016. The subjects were divided into 2 groups based on the type of risk calculator used: conventional and SNU-PCRC group. In the SNU-PCRC group, prostate biopsy was recommended when the probability of SNU-PCRC was more than 30%. Results: The SNU-PCRC group had significantly smaller prostate volume (p=0.010) and significantly more digital rectal examination and transrectal ultrasonography (TRUS) abnormalities (p=0.011 and p=0.010, respectively). Overall detection (71.9% vs. 32.1%) and high-risk cancer detection rates (40.6% vs. 19.3%) were significantly higher in the gray zone (prostate-specific antigen=4-10 ng/mL) (p<0.001 and p=0.006). The group with prostate cancer risk ≥30% on the SNU-PCRC compared to <30% group, overall detection rate of 72.3% versus 30.2% and high-risk detection rate of 60.6% versus 18.3% were significantly different (p<0.001 and p<0.001). Applying the SNU-PCRC to the conventional group could avoid unnecessary prostate biopsy in 50.6%. Conclusions SNU-PCRC is clinically useful to reduce unnecessary prostate biopsy and increase overall detection rate and high-risk cancer detection rate.

Purpose: Obstructive uropathy due to a ureteral obstruction is one of the most common diseases of the urinary tract, and can lead to severe renal injury and ureteral damage. This study performed to elucidate the histological findings and serial changes in the apoptotic and proliferative phenomena in the pathogenesis of ureteral damage during the course of obstructive uropathy in ligated rat ureters. Materials and Methods: After unilateral ligation of the ureter, each group of five Sprague-Dawley rats was sacrificed, and examined 1, 5, 10, 15, 20, 25, 30 and 35 days after ligation: five rats with normal ureters were also examined as controls. The cell proliferation and apoptosis were detected with proliferating cell nuclear antigen (PCNA) immunohistochemistry and a terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) in situ nick-end labeling (TUNEL) study, respectively, in 45 Sprague-Dawley rats. Results: The epithelial layer was thickened in the 5 day-obstructed ureters (DOUs). The severity of thickening of the fibrous and smooth muscle layers progressed consistently to the 15 DOUs, which was maintained until day 35. The expression of PCNA in the epithelial layer was present in every ureter, with a significant increase of labeled cells in the 1 and 5 DOUs. The expressions of PCNA in the fibrous and smooth muscle layers were present from day 10 after ligation and maintained until day 20, but then significantly declined at 25 DOUs. TUNEL-positive cells were shown in the epithelial layer in the 10, 15, 20, 25, 30 and 35 DOUs. The mean numbers of TUNEL-positive cells in the 20, 25 and 30 DOUs were significantly higher than those in the 10 DOUs, and reached their peak in the 25 DOUs. Positive cells were shown in the fibrous and smooth muscle layers in the 25, 30 and 35 DOUs. Conclusions: Apoptosis and cell proliferation may play an important role in the pathogenesis of ureteral damage in obstructed ureters. The peak of apoptosis was shown in the 25 DOUs.
Animals ; Apoptosis ; Cell Proliferation ; Deoxyuridine ; DNA Nucleotidylexotransferase ; Immunohistochemistry ; In Situ Nick-End Labeling ; Ligation ; Muscle, Smooth ; Proliferating Cell Nuclear Antigen ; Rats* ; Rats, Sprague-Dawley ; Ureter* ; Ureteral Obstruction ; Urinary Tract

Purpose: The use of gallium-68 prostate-specific membrane antigen-11 positron emission tomography/computed tomography (Ga-68 PSMA-11 PET/CT) is becoming increasingly common among men with prostate cancer (PCa). However, it remains uncertain which patients will derive the most benefit, and there is a scarcity of real-world data regarding its impact on altering treatment plans. This study investigated which patients would most benefit from Ga-68 PSMA-11 PET/CT, focusing on detection rates and changes in treatment strategies, drawing from a single-center experience. Materials and Methods: In total, 230 men with PCa who underwent Ga-68 PSMA-11 PET/CT between November 2021 and August 2022 were included in this retrospective study. The patients were classified into 5 groups based on their disease status: group 1, further work-up for high-risk localized PCa; group 2, de novo metastatic PCa; group 3, biochemical recurrence after definitive treatment; group 4, castration-resistant PCa; group 5, others. The positivity rate, positive lesions, predictive value of lymph node metastases, comparison with conventional images, and treatment changes after Ga-68 PSMA-11 PET/CT were analyzed in each group. Results: Of the 230 patients, 40 (17.4%), 20 (8.7%), 77 (33.5%), 76 (33.0%), and 17 (7.4%) were classified into groups 1–5, respectively. Ga-68 PSMA-11 PET/CT showed lesions in 74.8% of patients, and the optimal cutoff value for PSA was 1.99 ng/mL. Lesions not observed on conventional imaging were found in 62 patients (33.2%). In 38 patients (13.5%), treatment was changed due to Ga-68 PSMA-11 PET/CT. Conclusions These real-world data suggest that Ga-68 PSMA-11 PET/CT may be clinically useful for various disease conditions, as substantial stage migration and subsequent treatment changes occur in men with PCa. However, the prognostic impact of this modality remains unclear; thus, a well-designed prospective study is needed to address this issue.