Cheol Yong Yoon

Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase.

Recently, pegylated arginine deiminase (ADI; EC 3.5.3.6) has been used to treat the patients with hepatocellular carcinoma or melanoma, in which the level of argininosuccinate synthetase (ASS) activity is low or undetectable. The efficacy of its antitumor activity largely depends on the level of intracellular ASS, which enables tumor cells to recycle citrulline to arginine. Thus, we examined the expression levels of ASS in various cancer cells and found that it is low in renal cell carcinoma (RCC) cells, rendering the cells highly sensitive to arginine deprivation by ADI treatment. Immunohistochemical analysis revealed that in biopsy specimens from RCC patients (n = 98), the expression of ASS is highly demonstrated in the epithelium of normal proximal tubule but not seen in tumor cells. Furthermore, RCC cells treated with ADI showed remarkable growth retardation in a dose dependent manner. ADI also exerted in vivo antiproliferative effect on the allografted renal cell carcinoma (RENCA) tumor cells and prolonged the survival of tumor‐bearing mice. Histological examination of the tumors revealed that tumor angiogenesis and vascular endothelial growth factor (VEGF) expression were significantly diminished by ADI administration. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of RCC in ways of inhibitions of arginine availability and neovascularization.

Prevalence and Clinical Features of Detrusor Underactivity among Elderly with Lower Urinary Tract Symptoms: A Comparison between Men and Women

Purpose To identify the prevalence and clinical features of detrusor underactivity (DU) in elderly men and women presenting with lower urinary tract symptoms (LUTS). Materials and Methods We reviewed 1,179 patients aged over 65 years who had undergone a urodynamic study for LUTS with no neurological or anatomical conditions. DU was defined as a bladder contractility index <100 and a maximal flow rate (Qmax) ≤12 ml/s combined with a detrusor pressure at Qmax ≤10 cmH2O for men and women, respectively. Results Of the patients, 40.2% of men and 13.3% of women were classified as having DU (p<0.001). Types of clinical symptoms were not significantly different between patients with and without DU. In men, whereas the prevalence of bladder outlet obstruction (BOO) was constant across the age spectrum, the prevalence of DU and detrusor overactivity (DO) increased with age, and 46.5% of men with DU also had DO or BOO. In women, the prevalence of DU also increased with age, and the trend was more remarkable in women aged over 70 years. DU was accompanied by DO or urodynamic stress urinary incontinence (USUI) in 72.6% of the women with DU. Women with DU were found to have lower cystometric capacity and exhibited a greater incidence of reduced compliance than did women without DU. Conclusions DU was a common mechanism underlying LUTS in the elderly population, especially in men. One half of the men and three quarters of the women with DU also had other pathologies such as DO, BOO, or USUI.

Application of the Epstein criteria for prediction of clinically insignificant prostate cancer in Korean men

Study Type – Prognosis (case series)
Level of Evidence 4

NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells

The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. In this study, we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 μM/ml2% indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.

The Histone Deacetylase Inhibitor Trichostatin A Synergistically Resensitizes a Cisplatin Resistant Human Bladder Cancer Cell Line

PURPOSE Cisplatin is the mainstay of treatment for advanced bladder cancer. However, intrinsic or acquired resistance to cisplatin is common, which severely limits its therapeutic potential. We determined the synergistic antitumor effect of cisplatin and the histone deacetylase inhibitor trichostatin A in cisplatin resistant human bladder cancer cells. MATERIALS AND METHODS The cisplatin resistant human bladder cancer cell line T24R2 was exposed to cisplatin and/or trichostatin A. Tumor cell proliferation was examined by cell counting kit assay. Synergism between 2 drugs was examined by the combination index. Changes in cell cycle and apoptosis were determined by flow cytometry. We analyzed the expression of caspase-3, 8 and 9, poly(adenosine diphosphate-ribose) polymerase, p21WAF1/CIP1, cyclin A, B1 and D1, Cdc2c, p-Cdc2c, Cdc25c, p-Cdc25c, cytochrome c, p-Akt, t-Akt, Bcl-2, Bax, Bad, vascular endothelial growth factor and fetal liver kinase-1 by Western blot and colorimetric assay. RESULTS Based on the combination index and isobole analysis of the Cell Counting Kit-8 assay we observed a strong synergistic antitumor effect between cisplatin and trichostatin A, allowing a 3.5 and 4.9-fold dose reduction in cisplatin and trichostatin A, respectively, while achieving an estimated 90% kill of T24R2 cells. The underlying mechanism could be synergistic cell cycle arrest, induction of caspase mediated apoptosis or up-regulated expression of pro-apoptotic Bad and Bax. CONCLUSIONS Results indicate that trichostatin A may synergistically enhance the antitumor effect of cisplatin and resensitize cisplatin resistant bladder cancer cells. These findings suggest the potential use of histone deacetylase inhibitor as a combination agent to enhance the antitumor effect of cisplatin in patients with advanced bladder cancer.

Sunitinib Malate Synergistically Potentiates Anti-Tumor Effect of Gemcitabine in Human Bladder Cancer Cells

Purpose Sunitinib malate (Sutent; Pfizer, New York, NY, USA) is a highly selective multi-targeted agent and has been reported to have potent anti-tumor effects against various tumors, including renal cell carcinoma and gastrointestinal stromal tumors. In this study, we explored in vitro the anti-tumor effect and related molecular mechanisms of sunitinib malate against human bladder cancer cell lines. We also determined the synergistic anti-tumor effect between sunitinib and conventional cytotoxic drugs, cisplatin and gemcitabine, in bladder cancer cells. Materials and Methods Six human cancer cell lines (HTB5, HTB9, T24, UMUC14, SW1710, and J82) were exposed to an escalating dose of sunitinib alone or in combination with cisplatin/gemcitabine, and the cytotoxic effect of the drugs was examined by CCK-8 assay. The synergistic effect between sunitinib and cisplatin/gemcitabine was determined by the combination index (CI) and clonogenic assay. Alterations in cell cycle (cyclin D, B1), survival (p-Akt, t-Akt), and apoptosis (Bax, Bad) regulator expression were analyzed by Western blotting. Results Like cisplatin and gemcitabine, sunitinib exerted a dose- and time-dependent anti-tumor effect in bladder cancer cells. However, sunitinib exhibited entirely different sensitivity profiles from cisplatin and gemcitabine. Sunitinib suppressed the expression of cyclin B1, p-Akt, and t-Akt while augmenting the expression of cyclin D and pro-apoptotic Bax and Bad in HTB5 cells. Analysis of the drug combination by the isobolic method and clonogenic assay revealed that sunitinib acts in synergy with gemcitabine in HTB5 cells. Conclusions These results indicate that sunitinib malate has a potent anti-tumor effect and may synergistically enhance the anti-tumor effect of gemcitabine in human bladder cancer cells.

Prognostic significance of undetectable ultrasensitive prostate-specific antigen nadir after radical prostatectomy.

OBJECTIVES To investigate the prognostic significance of undetectable ultrasensitive prostate-specific antigen (PSA) nadir in patients who received radical prostatectomy (RP) for prostate cancer. METHODS We reviewed records of 384 patients who received RP for prostate cancer and were followed for at least 2 years with ultrasensitive PSA testing. Undetectable ultrasensitive PSA level was defined as <0.001 ng/mL. Subjects were categorized according to PSA nadirs: <0.001 ng/mL (group 1), 0.001 ng/mL ≤ and < 0.02 ng/mL (group 2), 0.02 ng/mL ≤ and < 0.05 ng/mL (group 3), or ≥0.05 ng/mL (group 4). Multivariate analysis was performed to identify independent predictors of biochemical recurrence-free survival. A receiver operator characteristics (ROC) curve was used to assess performances of multivariate model in predicting biochemical recurrence. RESULTS Overall, 206 (53.6%) patients showed undetectable ultrasensitive PSA nadir. Subjects of groups 1, 2, 3, and 4 demonstrated significant differences in biochemical recurrence-free survivals (log rank P <.001). In multivariate analysis, undetectable ultrasensitive PSA nadir (P <.001) was observed to be an independent predictor of biochemical recurrence-free survival along with preoperative PSA level (P = .030), pathologic stage (P = .014), and pathologic Gleason score (P = .042). Area under the ROC curve demonstrating predictive performances of the multivariate model, which included ultrasensitive PSA nadir, was significantly larger than that of the model without it (P <.001). CONCLUSIONS Our results demonstrated that undetectable ultrasensitive PSA nadir is a useful predictor of biochemical recurrence-free survival among contemporary patients who received RP for prostate cancer.

Is body mass index associated with pathological outcomes after radical prostatectomy in Korean men

Study Type – Therapy (case series)
Level of Evidence 4

Effect of the dual 5α-reductase inhibitor, dutasteride, on serum testosterone and body mass index in men with benign prostatic hyperplasia

Study Type – Therapy (RCT)
Level of Evidence 1b

Early recovery of urinary continence after radical prostatectomy: Correlation with vesico-urethral anastomosis location in the pelvic cavity measured by postoperative cystography

Objectives:  To determine the association of vesico‐urethral anastomosis location (VUAL) with early recovery of urinary continence (UC) after radical prostatectomy (RP).