Hongzoo Park

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.

Comparison of laparoscopic and open partial nephrectomies in t1a renal cell carcinoma: a korean multicenter experience.

Purpose We analyzed a series of patients who had undergone laparoscopic partial nephrectomies (LPNs) and open partial nephrectomies (OPNs) to compare outcomes of the two procedures in patients with pathologic T1a renal cell carcinomas (RCCs). Materials and Methods From January 1998 to May 2009, 417 LPNs and 345 OPNs were performed on patients with small renal tumors in 15 institutions in Korea. Of the patients, 273 and 279 patients, respectively, were confirmed to have pT1a RCC. The cohorts were compared with respect to demographics, peri-operative data, and oncologic and functional outcomes. Results The demographic data were similar between the groups. Although the tumor location was more exophytic (51% vs. 44%, p=0.047) and smaller (2.1 cm vs. 2.3 cm, p=0.026) in the LPN cohort, the OPN cohort demonstrated shorter ischemia times (23.4 min vs. 33.3 min, p<0.001). The LPN cohort was associated with less blood loss than the OPN cohort (293 ml vs. 418 ml, p<0.001). Of note, two patients who underwent LPNs had open conversions and nephrectomies were performed because of intra-operative hemorrhage. The decline in the glomerular filtration rate at the last available follow-up (LPN, 10.9%; and OPN, 10.6%) was similar in both groups (p=0.8). Kaplan-Meier estimates of 5-year local recurrence-free survival (RFS) were 96% after LPN and 94% after OPN (p=0.8). Conclusions The LPN group demonstrated similar rates of recurrence-free survival, complications, and postoperative GFR change compared with OPN group. The LPN may be an acceptable surgical option in patients with small RCC in Korea.

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).

Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration‐resistant prostate cancer

PTEN deletion, mutation or reduced expression occurs in 63% of metastatic prostate tumors, resulting in the activation of PI3K and its downstream targets, AKT and mTOR. Inhibition of the PI3K pathway results in upregulation of the MAPK pathway. Therefore, co‐administration of inhibitors of both pathways, GSK2126458 as a dual PI3K/mTOR inhibitor, and AZD6244 as a MEK inhibitor, is able to overcome resistance and increase anti‐tumor efficacy.

Efficacy and tolerability of combined medication of two different antimuscarinics for treatment of adults with idiopathic overactive bladder in whom a single agent antimuscarinic therapy failed

OBJECTIVE Recent studies have investigated a combination of two antimuscarinics for adult neurogenic bladder managed with clean intermittent catheterization or pediatric refractory overactive bladder (OAB). We assessed the efficacy and tolerability of this strategy in adults with idiopathic OAB. METHODS We reviewed 49 patients with idiopathic OAB who received combined antimuscarinic medication. Patients had serially received different kinds of antimuscarinics as monotherapy, but wished to take combined medication due to a lack of sufficient subjective improvement in urgency, even with dosage escalation. Efficacy was measured by changes of episodes of urgency, daytime voiding, nocturia and mean voided volume before and after the addition of the second antimuscarinic. RESULTS The mean duration of combined medication was 9.3 months. After adding the second antimuscarinic, urgency per day decreased from 3.8 to 1.9 (p < 0.001) and daytime voiding decreased from 10.4 to 7.4 (p < 0.001). The number of nocturia episodes and the mean voided volume also improved, although there was no statistical significance. Efficacy did not differ between the 29 cases, with non-selective and non-selective drugs and 20 cases with non-selective and M3 selective drugs. Thirty-three (67.3%) patients reported to have benefited from combined medication. Maximal flow rate and post-void residual volume did not change in either of the sexes. Eleven (22.4%) patients discontinued the combination due to continued ineffectiveness and dry mouth. CONCLUSION This retrospective study suggests that combined medication can help adults with refractory idiopathic OAB. Combined medication was tolerated in most of our patients.

Alteration of Antithrombin III and D-dimer Levels in Clinically Localized Prostate Cancer

Purpose We performed a comparative analysis of the plasma levels of antithrombin (AT) III, plasminogen, fibrinogen, and D-dimer among patients with and without clinically localized prostate cancer to investigate the clinical significance of the coagulation profile in prostate cancer. Materials and Methods A prospective study was performed in which plasma levels of AT III, plasminogen, fibrinogen, and D-dimer were assessed in patients before they underwent prostate biopsy. According to the results of the biopsy, the patients were categorized into the cancer group or the control group. Levels of the four coagulation factors were then compared between the cancer and control groups. Also, levels of the four coagulation factors were correlated with tumor stage and grade in the cancer group. Results The cancer group had significantly lower levels of AT III activity and higher plasma D-dimer levels than did the control group (p=0.007 and p=0.018, respectively). Within the cancer group, no significant differences were observed in the levels of AT III, plasminogen, fibrinogen, or D-dimer between those with a pathological Gleason score of ≥7 and otherwise. Regarding pathologic stage of prostate cancer, the subjects with organ-confined disease and those with extraprostatic extension of a tumor demonstrated no significant differences in the preoperative levels of the four coagulation factors analyzed. Conclusions Our results suggest that plasma levels of AT III and D-dimer are altered in patients with prostate cancer. Further study is needed to elucidate the underlying mechanism and clinical significances of such a phenomenon among patients with clinically localized prostate cancer.

Side-effects of protein kinase inhibitors on ion channels

Protein kinases are one of the largest gene families and have regulatory roles in all aspects of eukaryotic cell function. Modulation of protein kinase activity is a desirable therapeutic approach for a number of human diseases associated with aberrant kinase activity, including cancers, arthritis and cardiovascular disorders. Several strategies have been used to develop specific and selective protein kinase modulators, primarily via inhibition of phosphorylation and down-regulation of kinase gene expression. These strategies are effective at regulating intracellular signalling pathways, but are unfortunately associated with several undesirable effects, particularly those that modulate ion channel function. In fact, the side-effects have precluded these inhibitors from being both useful experimental tools and therapeutically viable. This review focuses on the ion channel side-effects of several protein kinase inhibitors and specifically on those modulating K+, Na+ and Ca2+ ion channels. It is hoped that the information provided with a detailed summary in this review will assist the future development of novel specific and selective compounds targeting protein kinases both for experimental tools and for therapeutic approaches.

A nuclear polyhedrosis virus ofHyphantriacunea replicatesinvitro

SummaryA nuclear polyhedrosis virus ofHyphantriacunea replicated successfully in theTrichoplusiani cell line. Restriction endonuclease analysis of the viral DNA obtained from infected cell culture showed the same general homogeneity as that from virus isolated from diseased host larvae. Electron microscopic observations showed that the occluded virus from cell culture consists of rod-like nucleocapsids (31×320 nm) enveloped in aggregates and embedded in polyhedral inclusion bodies from 0.6 to 2.5 μm in diameter.

Diagnostic Performance of %[-2]proPSA and Prostate Health Index for Prostate Cancer: Prospective, Multi-institutional Study

Background We evaluated the clinical performance of [-2]proPSA (p2PSA) and its derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) in Korean men. Methods A total of 246 men with total prostate-specific antigen (tPSA) ≥ 3.5 ng/mL who underwent their first prostate biopsy were included in this prospective, multicenter, observational study. Diagnostic accuracy of tPSA, free-to-total PSA ratio (%fPSA), p2PSA, %p2PSA, and the Beckman Coulter prostate health index (PHI) was assessed by receiver operating characteristic curve analyses and logistic regression analyses. Results Overall, PCa was detected in 125 (50.8%) subjects. In men with tPSA 3.5–10 ng/mL, the detection rate of PCa was 39.4% (61/155). In this group, PHI and %p2PSA were the most accurate predictors of PCa and significantly outperformed tPSA and %fPSA; area under the curve for tPSA, %fPSA, %p2PSA, and PHI was 0.56, 0.69, 0.74, and 0.76, respectively. PHI was also the strongest predictor of PCa with Gleason score ≥ 7. Conclusion This study demonstrates the superior clinical performance of %p2PSA and PHI in predicting the presence and aggressiveness of PCa in Korean men. The %p2PSA and PHI appear to improve detection of PCa and provide prognostic information.

Abstract LB-78: Synergistic effect of combination of MEK and phosphatidylinositol 3-kinase inhibitor on cell death in human prostate cancer DU145 cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Although chemotherapy has been used in castration-resistant prostate cancers (CRPCs) for a number of years, only limited improvement in survival is observed. Therefore, novel targeted therapeutic approaches must be developed for the treatment of CRPC. Currently, a wide range of small-molecular kinase inhibitors have been developed that target signaling pathways for survival, and inhibitors for MEK and PI3 kinase are currently being evaluated in clinical trials. To evaluate whether the combination treatment with MEK and PI3 kinase inhibitors is synergistic in prostate cancers, we used AZD6244 and a compound of GlaxoSmithkline (Smithkline) that inhibit MEK and PI3 kinase respectively. The combination of AZD6244-Smithkline showed synergistic anti-proliferative effect on growth of prostate cancer cells compared with the single treatment. In addition, a combination treatment induced apoptotic cell death, cleavage of caspase-9, caspase-3, and PARP synergistically. A significant increase in apoptosis was detected by annexin V-PI staining in DU145 cells after combined treatment compared with the single treatment. This study suggests that the combination with AZD6244 and Smithkline has a significant synergistic effect on cell growth in CRPC DU145 cells via apoptotic pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-78. doi:1538-7445.AM2012-LB-78