Feasibility of metronomic chemotherapy with tegafur-uracil, cisplatin, and dexamethasone for docetaxel-refractory prostate cancer.

Objectives: To evaluate the efficacy of tegafur-uracil (UFT), a prodrug of 5-fluorouracil, plus cisplatin and dexamethasone in patients with docetaxel-refractory prostate cancers. Methods: Twenty-five patients with docetaxel-refractory prostate cancer were administered oral UFT plus intravenous cisplatin (UFT-P therapy) and dexamethasone. Treatment responses were assessed monthly via prostate-specific antigen (PSA) level measurements. Treatment-related adverse events and overall survival were also assessed. Results: UFT-P therapy resulted in decreased PSA levels in 14 (56%) patients and increased PSA levels in 11 (44%). In patients with increased PSA levels, 7 (64%) of the 11 patients displayed decreased PSA doubling times. The UFT-P therapy response rate was 84% (21/25 patients). Imaging studies revealed that tumor shrinkage during UFT-P therapy occurred in 1 patient in whom bilateral hydronephrosis caused by lymph node metastasis improved. The median survival time from docetaxel initiation was 36 months. In UFT-P-treated patients, the median PSA progression and overall survival times were 6 and 14 months, respectively. UFT-P treatment-related adverse events were mild diarrhea, general fatigue, and anorexia. Treatment was not discontinued for any of the patients. UFT-P therapy did not cause serious hepatic or renal dysfunction or pancytopenia. Conclusions: UFT-P therapy is a safe and effective treatment for patients with docetaxel-refractory prostate cancer, although large-scale, multicenter, prospective studies are needed to validate these findings.

Clinical impact of palliative treatment using octreotide for inoperable malignant bowel obstruction caused by advanced urological cancer.

Malignant bowel obstruction (MBO), an occasional complication in patients with advanced urological cancer, causes gastrointestinal symptoms such as nausea and vomiting leading to suffering which severely impairs quality of life (QOL). Drug therapy, especially octreotide, a synthetic analog of somatostatin, is reportedly effective in controlling the symptoms of MBO. In the present study, we administered octreotide to urological cancer patients with MBO and evaluated the improvement of subjective symptoms, oral intake, and nasogastric intubation. Fourteen terminally ill urological cancer patients suffering with MBO were included (age range 55-92, 10 male, 4 female). Octreotide was administered at 300µg/day to those patients subcutaneously as a continuous injection. Significant improvements in subjective symptoms were observed in thirteen patients (92.8%), and ten patients (71.4%) were able to resume oral intake. Four patients required nasogastric drainage before the administration of octreotide, but nasogastric intubation was discontinued in all these cases after the use of octreotide. Early initiation of octreotide resulted in better improvement of MBO symptoms, and no adverse event was observed in any of the patients. These results revealed that 300µg/day dose of octreotide is safe and effective for managing gastrointestinal symptoms of terminally ill urological cancer patients with MBO. We also recommend starting the treatment with ocreotide as soon as MBO is diagnosed.

Implications of greater short-term PSA recurrence with laparoscopic as compared to retropubic radical prostatectomy for Japanese clinically localized prostate carcinomas.

PURPOSE: There is ongoing discussion as to the necessity for certain surgical procedures being limited to high through-put institutions. To cast light on this question regarding use of open as compared to laparoscopic radical prostatectomy (LRP) the present study was conducted focusing on biochemical (PSA) recurrence-free survival of Japanese patients with clinically localized prostate carcinomas. MATERIALS AND METHODS: From April 2004 to December 2010 we identified 579 patients undergoing LRP (n=245) and retropubic radical prostatectomy (RRP) (n=334) who did not undergo immediate adjuvant therapy (radiation and/or hormonal) and whose PSA levels were lower than 25 ng/ml. Preoperative prostate specific antigen (PSA) level, clinical stage, biopsy Gleason score and pathological features were assessed and Kaplan-Meier estimates of biochemical recurrence (BCR)-free survival were compared. A Cox regression model analysis was performed to determine predictors of biochemical recurrence. RESULTS: Median follow up was 35 months(2- 115). On univariate analysis the LRP group had a slightly lower pathological T stage (p<0.001), higher biopsy Gleason score (p<0.001), but much more organ confined disease (p=0.001) than the RRP group. BCR-free survival did not significantly differ between LRP and RRP groups with preoperative PSA <6, clinical stage T1c,T2a, pathological stage T3 or more, biopsy Gleason score of 8 or more, pathological Gleason score of 6 or less and 8 or more, extra-capsular extension and negative surgical margin. The 3-year BCR-free survival rates were 91.0%(RRP) and 82.2%(LRP) (p<0.001). CONCLUSION: We conclude that in general LRP may be associated with a less positive outcome than BCR for resection of low risk prostate cancers. Therefore indications for LRP should be very carefully monitored.

Simple method of preventing postoperative inguinal hernia after radical retropubic prostatectomy.

OBJECTIVES: To establish a novel and simple method of preventing post-retropubic prostatectomy (RRP) inguinal hernia. Inguinal hernias occur in 8%-22% of men within 1-2 years of RRP. Although manipulation during RRP might weaken the normal fascia structure at the internal inguinal ring with the vas deferens, the exact mechanism of post-RRP inguinal hernia remains unknown. METHODS: Several surgeons performed RRP at our hospital on 271 patients between April 2004 and September 2009. Among these patients, post-RRP measures to prevent inguinal hernia were applied to 101 patients (group A) and not applied to 170 patients (group B). We released the bilateral spermatic cord from the peritoneum before suturing the wound, which should prevent the intestinal tract coated with the peritoneum from pushing through the internal inguinal tract. We compared the incidence of postoperative inguinal hernia between the 2 groups. RESULTS: The patients were followed up for an average of 11.6 (range: 2-22 months) and 23.9 (range: 23-24 months) months in groups A and B, respectively. Inguinal hernia developed in no patients in group A and in 20 (11.8%) in group B. The hernia-free rate was significantly lower in group B than group A. All postoperative inguinal hernias were indirect. The median interval between surgery and hernia diagnosis was 10.6 months (range, 2-24), and 16 patients (80%) were diagnosed within 12 months. CONCLUSIONS: We developed a simple method of preventing inguinal hernia after RRP. Our technique is simple enough to complete within a few minutes, and the outcome is excellent.

Peroxisome proliferator-activated receptor-gamma and growth inhibition by its ligands in prostate cancer.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is expressed in certain human cancers. Ligand-induced PPAR-gamma activation can result in growth inhibition and differentiation in these cancer cells; however, the precise mechanism for the anti-proliferative effect of PPAR-gamma ligands is not clear. METHODS: In this study, we examined the expression of PPAR-gamma in human prostate cancer and the effect of two PPAR-gamma ligands, 15 deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) and troglitazone, on prostate cancer cell growth. RESULTS: PPAR-gamma is frequently over-expressed in androgen independent prostate cancer cell lines and human prostate cancer tissues (22 of 47; 47%). Both 15d-PGJ2 and troglitazone inhibited proliferation and DNA synthesis of prostate cancer cell lines in a dose-dependent manner, and slightly increased the proportion of cells with S-phase DNA content. Prostate specific antigen (PSA) promoter reporter assays showed that troglitazone and 15d-PGJ2 down-regulated androgen stimulated reporter gene activity in prostate cancer cell lines LNCaP. Interestingly, LNCaP with troglitazone dramatically suppressed PSA protein expression without suppressing AR expression. CONCLUSIONS: Taken together, these results suggest that PPAR-gamma ligands may be a useful therapeutic agent for the treatment of prostate cancer.

Essential role of Chk1 in S phase progression through regulation of RNR2 expression.

Chk1 is an essential kinase for maintaining genome integrity and cell cycle checkpoints through phosphorylating several downstream targets. Recently, we demonstrated that Chk1 is also required for cell proliferation in somatic cells under unperturbed condition through regulating transcription of several genes. Here, we show that Chk1 is required for S phase progression and RNR2 is a critical downstream target of genes transcriptionally regulated by Chk1. Hence, although RNR2 expression reached maximum at S phase in the presence of Chk1, Chk1 depletion arrested the cell cycle at S phase and reduced RNR2 expression at both mRNA and protein levels. Ectopic expression of RNR2 failed to rescue the S phase arrest observed in Chk1 depleted cells, suggesting the presence of an additional Chk1-target(s) for completion of S phase other than RNR2. Therefore, our results suggest that Chk1 is required for DNA replication at least through regulating RNR2 gene transcription.

[Molecular targeted therapy for prostate cancer].

Androgen plays an important role in the growth of prostate cancer, but the molecular mechanism that underlies the development of resistance to anti-androgen therapy remains unknown. In this paper, we review the role of cell cycle regulators and steroid receptor co-activators for prostate cancer growth and survival. Cyclin E has been shown to increase the transactivation activity of the human androgen receptor and the proliferation of prostate cancer cells. On the other hand, p27 using an adenovirus vector was shown to reduce the size of tumors of human prostate cancer xenografts. Steroid receptor coactivator-3 (SRC-3) is often over-expressed in prostate cancers. Our results indicate that overexpression of SRC-3 can modulate the AKT (protein kinase B) signaling pathway and stimulate cell growth in prostate cancer. In contrast, down-regulation of SRC-3 expression by small interfering RNA suppresses cell growth.