Time to progression to castration-resistant prostate cancer after commencing combined androgen blockade for advanced hormone-sensitive prostate cancer.

PURPOSE: The aim of our retrospective study was to determine the time to progression to castration-resistant prostate cancer (CRPC) in prostate cancer patients who undergo combined androgen blockade (CAB), as well as their prognoses. MATERIALS AND METHODS: We examined the overall survival (OS) and disease-specific survival rates, as well as the time to CRPC development, in 387 patients who were treated with CAB for prostate cancer. The disease-specific survival rate and time to CRPC were stratified by prostate-specific antigen (PSA) levels, Gleason score (GS), and presence of metastasis at diagnosis. We designated high-risk patients as those satisfying at least two of the following three criteria: extent of disease of bone metastasis grade ≥2, presence of metastasis at diagnosis, and a GS ≥8. RESULTS: The 10- and 15-year OS rates were 74.0% and 50.4%, respectively, while the corresponding disease-specific survival rates were both 86.8%. Metastasis at diagnosis was an independent prognostic factor for disease-specific survival. The median time to CRPC development was 140.7 months. A PSA level ≥20 ng/mL, a GS ≥8, and the presence of metastasis at diagnosis were independent predictors of a shorter time to CRPC development. The 10-year disease-specific survival rate in the high-risk group was significantly lower than that in the low-risk group (approximately 74% vs. 98%), and the time to CRPC development was significantly shorter (median: 20.5 months vs. not reached). CONCLUSIONS: The time to CRPC development was shorter in high-risk prostate cancer patients with metastases. Such patients require alternative novel treatment modalities.

Dynamic pathways of selenium metabolism and excretion in mice under different selenium nutritional statuses.

The selenoprotein, cellular glutathione peroxidase (cGPx), has an important role in protecting organisms from oxidative damage through reducing levels of harmful peroxides. The liver and kidney in particular, have important roles in selenium (Se) metabolism and Se is excreted predominantly in urine and feces. In order to characterize the dynamics of these pathways we have measured the time-dependent changes in the quantities of hepatic, renal, urinary, and fecal Se species in mice fed Se-adequate and Se-deficient diets after injection of (82)Se-enriched selenite. Exogenous (82)Se was transformed to cGPx in both the liver and kidney within 1 h after injection and the synthesis of cGPx decreased 1 to 6 h and continued at a constant level from 6 to 72 h after injection. The total amount of Se associated with cGPx in mice fed Se-deficient diets was found to be less than in mice fed Se-adequate diets. This finding indicated that cGPx synthesis was suppressed under Se-deficient conditions and did not recover with selenite injection. Excess Se was associated with selenosugar in liver and transported to the kidney within 1 h after injection, and then excreted in urine and feces within 6 h after injection. Any excess amount of Se was excreted mainly as a selenosugar in urine.

Indirect antitumor effects of bisphosphonates on prostatic LNCaP cells co-cultured with bone cells.

Bisphosphonates are strong inhibitors of osteoclastic bone resorption in both benign and malignant bone diseases. The nitrogen-containing bisphosphonates (N-BPs) have strong cytotoxicity via inhibition of protein prenylation in the mevalonate pathway, and also demonstrate direct cytostatic and proapoptotic effects on prostate cancer cells. We confirmed the usefulness of a co-culture system comprised of prostatic LNCaP cells, ST2 cells (mouse-derived osteoblasts) and MLC-6 cells (mouse-derived osteoclasts) in vitro. N-BPs (pamidronate and zoledronic acid) inhibited both androgen receptor transactivation and tumor cell proliferation by suppressing the activities of both osteoclasts and osteoblasts with low-dose exposure. This indirect inhibition of prostate cancer cells via bone cells could be beneficial in treating prostate cancer patients with bone metastases.

Overexpression of orotate phosphoribosyl transferase in hormone-refractory prostate cancer.

Orotate phosphoribosyl transferase (OPRT) is the initial enzyme of 5-fluorouracil (5-FU) activation, in which 5-FU is converted to 5-fluorouridinemonophosphate. Dihydropyrimidine dehydrogenase (DPD) is a degrading enzyme that catabolizes 5-FU. In this study, we investigated the expression of these enzymes in normal prostate gland (NP), hormone-sensitive prostate cancer (HSPC) and hormone-refractory prostate cancer (HRPC). Forty-two prostatic tissue specimens were obtained from patients who had undergone prostate needle biopsies without any treatments or with PSA failure after initial androgen deprivation. The tissue samples derived from formalin-fixed, paraffin-embedded sections were made by laser-captured microdissection and from those RNA was extracted. The levels of OPRT and DPD mRNA expression were examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The level of OPRT mRNA expression in the HSPC or the HRPC specimens was significantly higher than that in the NP specimens. Immunohistochemical staining for OPRT revealed strong expression of OPRT in prostate cancer cells. There was a significant correlation between OPRT mRNA expression levels and the tumor pathological grade. Furthermore, the OPRT/DPD expression ratio, a powerful predictive factor to evaluate 5-FU sensitivity, in the HRPC group was significantly higher than that in the low grade HSPC group. Thus, 5-FU may be an effective option for some HRPC patients.

Distribution and dynamic pathway of selenium species in selenium-deficient mice injected with (82)Se-enriched selenite.

In order to elucidate Se metabolism in a living body, (82)Se-enriched selenite was injected intravenously into mice fed Se-adequate and -deficient diets. We studied the time-dependent changes in the distribution of the labeled Se in organs, red blood cells, and plasma. The total Se was determined by flow-injection ICPMS, and Se speciation analysis was conducted by micro-affinity chromatography coupled with low-flow ICPMS. Total Se in almost all organs, including liver, showed the maximum at 1 h after injection. From speciation analysis, exogenous (82)Se as Se-containing proteins other than selenoprotein P (Sel-P) (selenium containing albumin (SeAlb) and extra cellular glutathione peroxidase (eGPx)), peaked at 1 h and quickly decreased from 1 to 6 h after injection, whereas that as Sel-P, peaked at 6 h, and gradually decreased from 6 to 72 h after injection. We found that there were two pathways for the transfer of Se in mice; one was as SeAlb until 1 h after injection, and the other was as Sel-P from 6 to 72 h after injection.

Involvement of the estrogen receptor beta in genistein-induced expression of p21(waf1/cip1) in PC-3 prostate cancer cells.

BACKGROUND: Dietary genistein, a phytoestrogen derived from soybean, has been suggested as a chemopreventive agent for prostate cancer. Genistein has been reported to exert its anticancer effects via a variety of functional pathways, but the upstream signaling of molecules regulated by genistein remains unclear. In this study, estrogen receptor (ER) beta involvement in genistein-induced expression of cell cycle inhibitors in PC-3 prostate cancer cells was investigated. MATERIALS AND METHODS: The proliferation of PC-3 cells exposed to genistein was measured by the water-soluble tetrazolium salt (WST-1) proliferation assay. The expression of p21, p27 and ERbeta in the PC-3 cells was assessed by quantitative real-time reverse transcription-PCR. ERbeta silencing was performed using a small interfering RNA (siRNA). The transcriptional activity of the p21 promoter was determined by the luciferase reporter assay. RESULTS: Genistein caused marked inhibition of proliferative activity and induced the expression of p21 and ERbeta in the PC-3 cells. The siRNA against ERbeta suppressed the genistein-induced expression of p21 and reduced the transactivation activity of the p21 promoter induced by genistein. CONCLUSION: ERbeta is involved in genistein-induced expression of p21 in PC-3 cells.

[Effects of eicosapentaenoic acid on visceral fat and heart rate variability: assessment by power spectral analysis].

OBJECTIVES: Effects of eicosapentaenoic acid (EPA)on visceral fat storage and the autonomic nervous system were evaluated by abdominal computed tomography (measurement of visceral fat area) and power spectral analysis of heart rate variability, respectively. METHODS: The parameters of visceral fat area and heart rate variability were compared between the control group (n=74; conventional therapy) and the EPA group (n=91; conventional therapy plus EPA 1800 mg/day) during a 6-month period. The power spectral analysis of heart rate variability [low frequency component (LF), high frequency component (HF)and LF/HF] was performed on 256 sec taken after a 30-minute rest. RESULTS: Systolic and diastolic blood pressures significantly decreased (p < 0.0001 and p = 0.0076, respectively)but heart rate remained unchanged in the EPA group during the 6 months. In the control group, these parameters showed no change. The values of visceral fat area did not alter in either group but body weight significantly decreased in the EPA group (p = 0.0003). A sex difference was noted in the parameter of visceral fat area; in female patients, the change in the parameter was insignificant, but in male patients this tended to decrease from 162 +/- 60 to 152 +/- 65 cm2 (p = 0.0586) during the 6 months. Serum triglyceride decreased significantly in the EPA group (p = 0.0339) but not in the control group. The ratio of LF/HF in heart rate variability significantly decreased in the EPA group (p = 0.0004) and the decrease was especially prominent in male patients. The LF/HF ratio remained unchanged in the control group. This parameter correlates well with visceral fat area, but not with systolic blood pressure. CONCLUSIONS: The oral intake of purified EPA significantly reduced blood pressure without altering heart rate during the 6-month treatment. EPA suppressed sympathetic nerve activity without inducing any parasympathetic nerve activity. The direct anti-sympathetic action of EPA was inferred and its action was found unrelated to blood pressure decrease. In male patients, diminished visceral fat area may be associated with depression of sympathetic nerve activity.

[A case of adult Wilms' tumor --review of the Japanese literature].

The patient was a 23-year-old-woman who was referred to our hospital with chief complaints of right flank pain and macroscopic hematuria. Right radical nephrectomy was performed with the diagnosis of right renal cancer. Histopathological examination revealed Wilms' tumor of favorable histology, stage I according to the National Wilms Tumor Study classification. She received adjuvant chemotherapy consisting of actinomycin D and vincristine at another hospital. One year and three months later, she developed lung metastasis. She underwent partial pulmonary resection, and then received chemotherapy. She is presently disease-free more than forty months after the initial operation. Wilms' tumor is rare in adults and has a poor prognosis compared with that in children. We analyzed 112 cases in the Japanese literature from 1981 to 2004. The mean age was 36.9 years, with males and females equally affected. No difference was found between the left and right sides in frequency of tumor. We also examined the relationship between histological features and prognosis based on 43 Japanese reports. Twenty-two of the 43 (51%) cases had unfavorable histology. The 2-year survival rate with unfavorable histology was 18%, while that with favorable histology was 87%. The 2-year survival rates for stages under II and over III were 67% and 27%, respectively. Based on these findings, we conclude that the prognosis of adult Wilms' tumor is very poor since many patients have unfavorable histology and no effective treatment guidelines have been established.

Renal transplantation for the hemodialysis patient with axillofemoral bypass.

BACKGROUND: Axillofemoral bypass grafts are used in the treatment of aortoiliac occlusive disease caused by atherosclerosis. There have been no previous reports on renal transplantation used as treatment for chronic renal failure after an axillofemoral bypass graft being placed because of atypical coarctation of the aorta. METHODS: The patient was a 47-year-old woman who had received regular hemodialysis for 15 years. Axillofemoral bypass surgery was performed because of atypical coarctation of the aorta in October 1999. Three years after surgery, she underwent renal transplantation. RESULTS: Renal transplantation was successful, and helical computed tomography demonstrated patent graft bypass and good nephrographic effects of the renal artery. CONCLUSIONS: Even though dialysis patients with atypical coarctation of the aorta are treated with an axillofemoral bypass, it is possible for them to undergo regular renal transplantation, if part of the external or internal iliac artery is intact.

Renin mRNA expression and renal dysfunction in tacrolimus-induced acute nephrotoxicity.

Tacrolimus is a superior immunosuppressive agent and has markedly improved the short-term outcome of renal allografts. Despite the beneficial effects of maintaining immunotolerance in organ transplant recipients, it has well-characterized side effects on renal hemodynamics in the early phase. The mechanism of tacrolimus-induced acute nephrotoxicity is still unclear. The purpose of this study was to elucidate the role of renin-angiotensin system (RAS) in tacrolimus-induced acute nephrotoxicity. We examined the renal mRNA levels of renin in order to elucidate the relationship between plasma renin activity (PRA) and tacrolimus-induced renal dysfunction. Daily administration of tacrolimus (4 mg/kg/day) for 2 weeks in spontaneously hypertensive rats (SHR) significantly increased BUN and plasma creatinine (P-Cr) level, while endogenous creatinine clearance (Ccr) significantly decreased in tacrolimus treated rats. Regarding tubular function data, fractional excretion of Na (FENa) and fractional excretion of K were higher in the tacrolimus treated group. Renin mRNA levels in the renal cortex in tacrolimus treated rats significantly increased when compared to the vehicle-treated rats. Ccr level was inversely proportional to PRA, with a high correlation coeffecient. The rise in PRA significantly correlated with increase in FENa by liner regression. Therefore, the results indicate that RAS is involved in the tacrolimus-induced acute nephrotoxicity.