Laparoscopic Repair of a Ureterosciatic Hernia with Urosepsis.

Hernias of pelvic floor are very rare condition, and herniations of ureter into sciatic foramen are extremely rare condition which is globally reported only by 32 cases. Clinical aspects of ureterosciatic hernias appeared variously according to the degree of hydronephrosis, inflammation and infection of kidney due to ureter obstruction. Herein, we report our experience of laparoscopic repair in a patient with ureterosciatic hernia combined urosepsis.

Radical prostatectomy for clinically localized prostate cancer in patients aged 75 years or older: comparison with primary androgen deprivation therapy.

OBJECTIVE: To determine whether radical prostatetomy (RP) is suitable for prostate cancer patients with age ≥75 years in comparison to primary androgen deprivation therapy (PADT). PATIENTS AND METHODS: A cohort study was conducted in clinically localized prostate cancer patients with ≥75 years of age who underwent RP or PADT at six institutions from 2005 to 2013. Patients who had less than 12 months of follow-up, or received neoadjuvant or adjuvant therapy were excluded. We compared clinical characteristics, cancer-specific and overall survivals, and post-treatment complication rates between two groups. RESULTS: We included 92 and 99 patients in the RP and PADT groups, respectively. In survival analyses, there were no significant differences in cancer-specific and overall survivals (p = .302 and .995, respectively). The incidence of serious adverse events (cardio- or cerebrovascular event, or bone fracture) was higher in the PADT group (p = .001). Multivariable analysis showed that PADT had a worse effect on the serious adverse events (OR 10.12, p = .038). CONCLUSIONS: In selected elderly patients, RP was safe and effective for treatment of localized prostate cancer, as compared to PADT. Surgical treatment options should be considered in elderly patients with respect to life expectancy, rather than chronological age.

Quality of randomized controlled trials published in the International Urogynecology Journal 2007-2016.

INTRODUCTION AND HYPOTHESIS: Randomized controlled trials (RCTs) provide the best quality clinical evidence. The aim of this study was to assess the quality of RCTs published by the International Urogynecology Journal (IUJ) in 2007-2016. METHODS: RCTs in original articles were extracted from PubMed and IUJ homepage. Change in RCT quality over time was assessed with Jadad and van Tulder scales and Cochrane Collaboration's risk of bias tool (CCRBT). Jadad scores of 3-5 or van Tulder scores of >5 indicated high-quality RCTs. The effect on RCT quality of including funding source and institutional review board (IRB) approval statements and describing the intervention was assessed. In addition, changes in RCT topics over time were assessed. RESULTS: Annual RCT frequencies did not change significantly (6.7-15.7%): 36.1% and 25.7% described blinding and allocation concealment, respectively. Both tended to increase between 2013 and 2016, particularly 2013 and 2014. Funding statement inclusion (39.1% overall) and intervention description (78.2% overall) tended to increase steadily. IRB statement inclusion (60.4% overall) increased significantly (p < 0.01). Jadad scores and van Tulder rose significantly until 2014 (p < 0.01). Frequencies of high-quality RCTs tended to rise. CCRBT indicated that RCTs with a low risk of bias tended to increase until 2014. However, from 2015, Jadad scores, van Tulder, and CCRBT the low risk tended to decreased. RCTs with funding and IRB approval statements had higher Jadad and van Tulder scores than unfunded RCTs (p < 0.01 and p < 0.01, respectively). Intervention description did not associate with better quality. CONCLUSIONS: RCT quality improved over time, but a dip in quality was observed in 2015-2016 because of decreased blinding and allocation concealment.

Expression levels of heat shock protein 27 and cellular FLICE-like inhibitory protein in prostate cancer correlate with Gleason score sum and pathologic stage.

PURPOSE: Heat shock protein (HSP) 27 protects the cell by controlling apoptosis and immune reactions, and c-FLIP (cellular-FLICE inhibitory protein) inhibits apoptosis by inhibiting caspase-8 activity. We investigated the relationship of HSP27 and c-FLIP expression to prostate-specific antigen, Gleason score sum (GSS), and pathologic stage. MATERIALS AND METHODS: Samples from 163 patients between May 2004 and April 2010 were analyzed: 83 from patients that had underwent a radical prostatectomy, and 80 from those that underwent transurethral resection of the prostate to alleviate urinary symptoms from benign prostate hyperplasia. c-FLIP and HSP27 expression were observed by immunohistochemistry staining. Samples with less than 5% expression-positive cells were scored as 1, with 5%-50% were scored as 2, and with more than 50% were scored as 3. Local reactions were identified as 0.5 and evaluated. RESULTS: Both the presence of HSP27 within the tumor and the number of cancer cells positive for HSP27 were significantly correlated to GSS and pathologic stage (p<0.001, p=0.001, p<0.001, p<0.001). The same was true for c-FLIP expression (p<0.001). GSS was more highly correlated to HSP27 expression than to c-FLIP expression (r=0.814 for HSP27, r=0.776 for c-FLIP), as was pathologic stage (r=0.592 for HSP27, r=0.554 for c-FLIP). CONCLUSIONS: In prostate cancer, higher GSS and a more advanced pathologic stage were associated with a higher likelihood of having a HSP27-positive tumor and more HSP27-positive tumor cells. HSP27 expression was correlated with GSS and prostate cancer stage. A more advanced pathologic stage corresponded to a higher likelihood of having a c-FLIP-positive tumor and more c-FLIP-positive tumor cells. HSP27 expression had a higher correlation with prostate cancer stage and GSS than c-FLIP expression did.

Silodosin for the treatment of clinical benign prostatic hyperplasia: safety, efficacy, and patient acceptability.

α1-Adrenergic receptor antagonists are commonly used to treat male lower urinary tract symptoms and benign prostatic hyperplasia (BPH). We performed a literature search using PubMed, Medline via Ovid, Embase, and the Cochrane Library databases to identify studies on the treatment of BPH by silodosin. Silodosin is a novel α1-adrenergic receptor antagonist whose affinity for the α1A-adrenergic receptor is greater than that for the α1B-adrenergic receptor. Therefore, silodosin does not increase the incidence of blood pressure-related side effects, which may result from the inhibition of the α1B-adrenergic receptor. Patients receiving silodosin at a daily dose of 8 mg showed a significant improvement in the International Prostate Symptom Score and maximum urinary flow rate compared with those receiving a placebo. Silodosin also improved both storage and voiding symptoms, indicating that silodosin is effective, even during early phases of BPH treatment. Follow-up extension studies performed in the United States, Europe, and Asia demonstrated its long-term safety and efficacy. In the European study, silodosin significantly reduced nocturia compared to the placebo. Although retrograde or abnormal ejaculation was the most commonly reported symptom in these studies, only a few patients discontinued treatment. The incidence of adverse cardiovascular events was also very low. Evidence showing solid efficacy and cardiovascular safety profiles of silodosin will provide a good solution for the treatment of lower urinary tract symptoms associated with BPH in an increasingly aging society.

A comparison of epididymectomy with vasectomy reversal for the surgical treatment of postvasectomy pain syndrome.

PURPOSE: To compare the outcome of epididymectomy and vasectomy reversal (VR) in patients with postvasectomy pain syndrome (PVPS) who required surgical treatment. METHODS: A total of 50 patients with PVPS who underwent epididymectomy or VR between January 2000 and January 2010 were included retrospectively. Of these, 36 (72.0%) patients completed the study questionnaire. These 36 patients completed the questionnaire either during attendance at the outpatient clinic or during a telephone interview. Twenty patients (22 cases) underwent epididymectomy, and sixteen patients (17 cases) underwent VR. Analyses were performed for (1) preoperative clinical findings, (2) preoperative and postoperative visual analogue pain scale (VAPS) scores, (3) patency and pregnancy rate in VR group, and (4) patient satisfaction with surgical treatment. RESULTS: The mean age was 48.28 ± 11.27 years, and the mean period of follow-up was 3.58 years (0.15-10.03). The mean VAPS score was 6.78 ± 0.93 preoperatively and 1.13 ± 0.72 postoperatively (p < 0.001). The difference in the mean preoperative and postoperative VAPS scores was 6.00 ± 1.34 (3-8) in the epididymectomy group and 5.50 ± 1.03 (4-8) in the VR group. However, this difference was not statistically significant (p = 0.227). No significant difference in satisfaction with surgical outcome was observed between the epididymectomy and the VR groups (p = 0.124). CONCLUSIONS: In PVPS patients requiring surgical treatment, no significant difference was observed between the epididymectomy and VR groups in either the reduction in pain or the degree of patient satisfaction with surgical outcome. Selection of the optimal surgical procedure may be dependent on specific patient characteristics.

The role of transurethral resection of the prostate for patients with an elevated prostate-specific antigen.

PURPOSE: The aim of this study was to define the clinical significance of transurethral resection of the prostate (TURP) in patients with benign prostate hyperplasia (BPH) and an elevated prostate-specific antigen (PSA) level. METHODS: We retrospectively evaluated patients with BPH, lower urinary tract symptoms (LUTS; International Prostate Symptom Score [IPSS]≥8), an elevated serum PSA level (≥4 ng/mL), and previous negative transrectal ultrasonography (TRUS) guided prostate biopsy. The PSA level after TURP was monitored by long-term follow-up. The tumor detection rate on resected prostate tissue, IPSS, maximal urinary flow rate (Qmax), and postvoid residual urine (PVR) were analyzed. RESULTS: One-hundred and eighty-six patients were enrolled. Histological examination of resected tissue by TURP revealed prostate cancer in 12 of these patients (6.5%). Among 174 patients without prostate cancer, the mean PSA level and the PSA normalization rate in 112 patients followed up at postoperative day (POD) 3 months were 1.26±0.13 ng/mL and 94.6%, respectively. The mean PSA level and the PSA normalization rate were 1.28±1.01 ng/mL and 95.7% in 47 patients at 1st year, 1.17±0.82 ng/mL and 97.1% in 34 patients at second years, and 1.34±1.44 ng/mL and 97.2% in 36 patients at third years of TURP. One patient showed a dramatic increase in the PSA level was diagnosed with prostate cancer at 7 years after TURP. IPSS, quality of life, Qmax, and PVR were improved significantly at POD 3 months compared to baseline (P<0.05), respectively. CONCLUSIONS: TURP significantly reduced the serum PSA level, which was maintained for at least 3 years. This could be helpful to screen the prostate cancer using PSA value in the patient with previous negative biopsy and elevated PSA. In addition, TURP improves IPSS, Qmax, and PVR in patients with BPH, moderate LUTS, and an elevated PSA level.

Effect of transurethral resection of the prostate based on the degree of obstruction seen in urodynamic study.

PURPOSE: We retrospectively investigated the effect of transurethral resection of the prostate (TURP) on the basis of the degree of obstruction seen in preoperative urodynamic study in patients with benign prostatic hyperplasia (BPH) who complained of lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: The subjects of this study were 285 patients who were diagnosed with BPH with LUTS and who subsequently underwent TURP. The Abrams-Griffiths number was calculated from the urodynamic results to divide the patients into the following groups: unobstructed, equivocal, and obstructed. There were 26 patients (9.1%) in the unobstructed group, 98 patients (34.4%) in the equivocal group, and 161 patients (56.5%) in the obstructed group. The preoperative and postoperative uroflowmetry, residual urine, International Prostate Symptom Score (IPSS), and quality of life (QoL) score were compared between the three groups to evaluate the outcome of the treatment. RESULTS: The reduction in the IPSS was 14.4 in the obstructed group, which was higher than the reductions of 12.7 in the equivocal group and 9.5 in the unobstructed group, but this difference was not statistically significant (p=0.227). The QoL score was also not significantly different across the three groups (p=0.533). The postoperative maximum flow rate was significantly improved in all three groups. The obstructed group had an improvement of 7.8±7.2 mL/s, which was higher than the improvement of 3.7±6.2 mL/s in the unobstructed group (p=0.049) but was not significantly different from the improvement of 5.6±6.9 mL/s in the equivocal group (p=0.141). CONCLUSIONS: TURP led to an improvement in the maximum flow rate and LUTS even in BPH patients without BOO. Therefore, TURP can be expected to improve LUTS in BPH patients without definite urodynamic obstruction.

Experience with robot-assisted laparoscopic radical prostatectomy at a secondary training hospital: operation time, treatment outcomes, and complications with the accumulation of experience.

PURPOSE: To investigate the learning curve and outcomes of robot-assisted laparoscopic radical prostatectomy (RALP) performed by a relatively lower volume surgeon at a secondary training hospital. MATERIALS AND METHODS: The medical records and the surgery video recordings of 100 patients who underwent RALP by a single surgeon between March 2010 and January 2013 were reviewed. The first 10 cases were grouped into period 1, cases 11 to 40 into period 2, cases 41 to 70 into period 3, and cases 71 to 100 into period 4. The interval between the operations, the operative time for each step of the surgery, the total console time, and the operative outcomes were investigated. RESULTS: The mean interval between surgeries was 10.6±9.3 days. The console time decreased progressively after the first 10 cases and reached under 3 hours after 75 cases. The time taken to begin dissection of the dorsal vein complex, for the division of the bladder neck, for lateral dissection with neurovascular bundle preservation, and for apex dissection decreased significantly with experience, although the time for vesicourethral anastomosis did not. The margin-positive rate of stage T2 patients was 27.4% (20/73), and the transfusion rate was 50% in period 1 patients and 3.3% in period 4 patients. No major complications occurred. CONCLUSIONS: It is difficult to shorten the learning curve of surgeons in secondary training hospitals owing to the smaller number of cases and the irregular surgical intervals. Although the operation time was relatively longer, the surgical outcome and complication rates were comparable with those of surgeons at larger hospitals.

Dual silencing of Hsp27 and c-FLIP enhances doxazosin-induced apoptosis in PC-3 prostate cancer cells.

We evaluated effect of dual gene silencing of Hsp27 and c-FLIP in doxazosin-induced apoptosis of PC-3 cell. After transfection using Hsp27 and c-FLIP siRNA mixture (dual silencing), doxazosin treatment was done at the concentrations of 1, 10, and 25 µ M. We checked apoptosis of PC-3 cells with and TUNEL staining. We also checked interaction between Hsp27 and C-FLIP in the process of apoptosis inhibition. Spontaneous apoptotic index was 5% under single gene silencing of Hsp27 and c-FLIP and 7% under dual silencing of Hsp27 and c-FLIP. When doxazosin treatment was added, apoptotic indices increased in a dose-dependent manner (1, 10, and 25 µ M): nonsilencing 10, 27, and 52%; Hsp27-silencing: 14, 35, and 68%; c-FLIP silencing: 21, 46, and 78%; dual silencing: 38, 76, and 92%. While c-FLIP gene expression decreased in Hsp27- silenced cells, Hsp27 gene expression showed markedly decreased pattern in the cells of c-FLIP silencing. The knockout of c-FLIP and Hsp27 genes together enhances apoptosis even under 1 µ M, rather than low concentration, of doxazosin in PC-3 cells. This finding suggests a new strategy of multiple knockout of antiapoptotic and survival factors in the treatment of late-stage prostate cancer refractory to conventional therapy.

Prevalence and risk factors of bladder neck contracture after radical prostatectomy.

PURPOSE: To evaluate the prevalence of bladder neck contracture (BNC) and its risk factors in patients undergoing radical prostatectomy in Korea. MATERIALS AND METHODS: We analyzed data from 488 patients with prostatic cancer who underwent radical prostatectomy performed by seven surgeons in seven hospitals, including 365 open radical prostatectomies (ORPs), 99 laparoscopic radical prostatectomies (LRPs), and 24 robot-assisted laparoscopic radical prostatectomies (RARPs). Patients with BNCs were compared with those without BNCs to identify the risk factors for BNC occurrence. RESULTS: Overall, BNCs occurred in 21 of 488 patients (4.3%): 17 patients (4.7%) who underwent ORP, 4 patients (4%) who underwent LRP, and no patients who underwent RARP. In the univariate analysis, men with BNCs had a longer length of time before drain removal (12 days vs. 6.8 days, p<0.001), which reflected urinary leakage through the vesicourethral anastomosis. In the multivariate analysis, the length of time before drain removal was the only predictor of BNC (odds ratio, 1.12; p=0.001). Intraoperative blood loss was higher in patients with BNC, but the difference was not statistically significant. CONCLUSIONS: The most significant factor related to BNC occurrence after radical prostatectomy in our study was the length of time before drain removal, which reflects urinary leakage from the vesicourethral anastomosis. The proper formation of a watertight anastomosis to decrease urinary leakage may help to reduce the occurrence of BNC.

Efficacy of alfuzosin after shock wave lithotripsy for the treatment of ureteral calculi.

PURPOSE: We evaluated the efficacy of alfuzosin for the treatment of ureteral calculi less than 10 mm in diameter after extracorporeal shock wave lithotripsy (ESWL). MATERIALS AND METHODS: A randomized, single-blind clinical trial was performed prospectively by one physician between June 2010 and August 2011. A total of 84 patients with ureteral calculi 5 to 10 mm in diameter were divided into two groups. Alfuzosin 10 mg (once daily) and loxoprofen sodium 68.1 mg (as needed) were prescribed to group 1 (n=41), and loxoprofen sodium 68.1 mg (as needed) only was prescribed to group 2 (n=44). The drug administration began immediately after ESWL and continued until stone expulsion was confirmed up to a maximum of 42 days after the procedure. RESULTS: Thirty-nine of 41 (95.1%) patients in group 1 and 40 of 43 (93.0%) patients in group 2 ultimately passed stones (p=0.96). The number of ESWL sessions was 1.34±0.65 and 1.41±0.85 in groups 1 and 2, respectively (p=0.33). The patients who required analgesics after ESWL were 8 (19.5%) in group 1 and 13 (30.2%) in group 2 (p=0.31). Visual analogue scale pain severity scores were 5.33±1.22 and 6.43±1.36 in groups 1 and 2, respectively (p=0.056). The time to stone expulsion in groups 1 and 2 was 9.5±4.8 days and 14.7±9.8 days, respectively (p=0.005). No significant adverse effects occurred. CONCLUSIONS: The use of alfuzosin in combination with ESWL seems to facilitate stone passage and to reduce the time of stone expulsion but does not affect the stone-free rate.

Assessments of the quality of randomized controlled trials published in International Journal of Urology from 1994 to 2011.

OBJECTIVES: Randomized controlled trials are one of the most reliable resources for assessing the effectiveness and safety of medical treatments. Low quality randomized controlled trials carry a large bias that can ultimately impair the reliability of their conclusions. The present study aimed to evaluate the quality of randomized controlled trials published in International Journal of Urology by using multiple quality assessment tools. METHODS: Randomized controlled trials articles published in International Journal of Urology were found using the PubMed MEDLINE database, and qualitative analysis was carried out with three distinct assessment tools: the Jadad scale, the van Tulder scale and the Cochrane Collaboration Risk of Bias Tool. The quality of randomized controlled trials was analyzed by publication year, type of subjects, intervention, presence of funding and whether an institutional review board reviewed the study. RESULTS: A total of 68 randomized controlled trial articles were published among a total of 1399 original articles in International Journal of Urology. Among these randomized controlled trials, 10 (2.70%) were from 1994 to 1999, 23 (4.10%) were from 2000 to 2005 and 35 (4.00%) were from 2006 to 2011 (P = 0.494). On the assessment with the Jadad and van Tulder scale, the numbers and percentage of high quality randomized controlled trials increased over time. The studies that had institutional review board reviews, funding resources or that were carried out in multiple institutions had an increased percentage of high quality articles. CONCLUSIONS: The numbers and percentage of high-quality randomized controlled trials published in International Journal of Urology have increased over time. Furthermore, randomized controlled trials with funding resources, institutional review board reviews or carried out in multiple institutions have been found to be of higher quality compared with others not presenting these features.

Benign prostatic hyperplasia: from bench to clinic.

Benign prostatic hyperplasia (BPH) is a prevalent disease, especially in old men, and often results in lower urinary tract symptoms (LUTS). This chronic disease has important care implications and financial risks to the health care system. LUTS are caused not only by mechanical prostatic obstruction but also by the dynamic component of obstruction. The exact etiology of BPH and its consequences, benign prostatic enlargement and benign prostatic obstruction, are not identified. Various theories concerning the causes of benign prostate enlargement and LUTS, such as metabolic syndrome, inflammation, growth factors, androgen receptor, epithelial-stromal interaction, and lifestyle, are discussed. Incomplete overlap of prostatic enlargement with symptoms and obstruction encourages focus on symptoms rather than prostate enlargement and the shifting from surgery to medicine as the treatment of BPH. Several alpha antagonists, including alfuzosin, doxazosin, tamsulosin, and terazosin, have shown excellent efficacy without severe adverse effects. In addition, new alpha antagonists, silodosin and naftopidil, and phosphodiesterase 5 inhibitors are emerging as BPH treatments. In surgical treatment, laser surgery such as photoselective vaporization of the prostate and holmium laser prostatectomy have been introduced to reduce complications and are used as alternatives to transurethral resection of the prostate (TURP) and open prostatectomy. The status of TURP as the gold standard treatment of BPH is still evolving. We review several preclinical and clinical studies about the etiology of BPH and treatment options.

Comparison of an Indwelling Period Following Ureteroscopic Removal of Stones between Double-J Stents and Open-Ended Catheters: A Prospective, Pilot, Randomized, Multicenter Study.

PURPOSE: The aim of this study was to evaluate whether long-term, postoperative ureteral stenting is necessary after ureteroscopic removal of stones (URS) during an uncomplicated surgical procedure. MATERIALS AND METHODS: We prospectively examined 54 patients who underwent URS for lower ureteral stones from February 2010 to October 2010. Inclusion criteria were a stone less than 10 mm in diameter, absence of ureteral stricture, and absence of ureteral injury during surgery. We randomly placed 5 Fr. open-tip ureteral catheters in 26 patients and removed the Foley catheter at postoperative day 1. The remaining 28 patients received double-J stents that were removed at postoperative day 14 by cystoscopy under local anesthesia. All patients provided visual analogue scale (VAS) pain scores at postoperative days 1, 7, and 14 and completed the storage categories of the International Prostate Symptom Score (IPSS) at postoperative day 7. RESULTS: The VAS scores were not significantly different on postoperative day 1 but were significantly smaller in the 1-day ureteral catheter group at postoperative days 7 and 14 (p<0.01). All of the storage categories of the IPSS were significantly lower in the 1-day ureteral stent group (p<0.01). The ratio of patients who needed intravenous analgesics because of severe postoperative flank pain was not significantly different between the two groups (p=0.81). No patients experienced severe flank pain after postoperative day 2, and no patients in either group had any other complications. CONCLUSIONS: One-day ureteral catheter placement after URS can reduce postoperative pain and did not cause specific complications compared with conventional double-J stent placement.

Analysis of prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors from the urology department and other departments.

PURPOSE: We analyzed the prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors (PDE5Is) in the urology department as well as in other departments of the general hospital. METHODS: We investigated the frequency of prescription of alpha-blockers and PDE5Is from 3 general hospitals from January 1, 2007 to December 31, 2009. For alpha-blockers, data were collected from patients to whom alpha-blockers were prescribed from among patients recorded as having benign prostatic hyperplasia according to the 5th Korean Standard Classification of Diseases. For PDE5Is, data were collected from patients to whom PDE5Is were prescribed by the urology department and by other departments. Alpha-blockers were classified into tamsulosin, alfuzosin, doxazosin, and terazosin, whereas PDE5Is were classified into sildenafil, tadalafil, vardenafil, udenafil, and mirodenafil. RESULTS: Alpha-blockers were prescribed to 11,436 patients in total over 3 years, and the total frequency of prescriptions was 68,565. Among other departments, the nephrology department had the highest frequency of prescription of 3,225 (4.7%), followed by the cardiology (3,101, 4.5%), neurology (2,576, 3.8%), endocrinology (2,400, 3.5%), pulmonology (1,102, 1.6%), and family medicine (915, 1.3%) departments in order. PDE5Is were prescribed to 2,854 patients in total over 3 years, and the total frequency of prescriptions was 10,558. The prescription frequency from the urology department was 4,900 (46.4%). Among other departments, the endocrinology department showed the highest prescription frequency of 3,488 (33.0%), followed by the neurology (542, 5.1%), cardiology (467, 4.4%), and family medicine (407, 3.9%) departments in order. CONCLUSIONS: A high percentage of prescriptions of alpha-blockers and PDE5Is were from other departments. For more specialized medical care by urologists is required in the treatment of lower urinary tract symptoms and erectile dysfunction.

New benzoxanthone derivatives as topoisomerase inhibitors and DNA cross-linkers.

We synthesized 12 benzoxanthone derivatives classified as three different groups based on the tetracyclic ring shapes and evaluated their pharmacological activities to find potential anticancer agents. In the cytotoxicity test, most compounds showed effective cancer cell growth inhibition against the HT29 and DU145 cell lines. Among the compounds tested, compound 19 was the most effective in the cancer cell lines tested. Compound 9 showed dual inhibitory activities against DNA relaxation by topoisomerases I and II. The% inhibition of compound 9 on topoisomerase I was comparable to that of camptothecin. Compound 9 efficiently blocked topoisomerase II function by almost threefold than etoposide at 20 microM. Compound 19 had selective topoisomerase II inhibitory activity at 100 microM. The DNA cross-linking test revealed that only compounds 8 and 19, which possess epoxy groups, cross-linked DNA duplex, while 14 did not. From the combined pharmacological results, we proposed that the target through which compound 19 inhibits cancer cell growth may be the DNA duplex itself and/or DNA-topoisomerase II complex.

Oxiranylmethyloxy or thiiranylmethyloxy-azaxanthones and -acridone analogues as potential topoisomerase I inhibitors.

A total of seven new oxyranylmethyloxy or thiiranylmethyloxy group substituted 5-azaxanthones and -acridones analogues were synthesized and tested for their biological activities for cancer cell lines and topoisomerases. Among the compounds, compound 5, 3-thiiranylmethyloxy-1-hydroxy-5-azaxanthone, showed effective topoisomerase I inhibitory activity, 50% and 27% inhibition ratio at 100 and 20muM, respectively. This result is the first finding of the function of 5-azaxanthone compounds for topoisomerase I inhibition and can provide a novel skeleton for the anticancer drug development process.