Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.

Sarcoidosis is a multisystem disorder that rarely involves the genitourinary tract. To date, only 59 cases of histologically proven sarcoidosis involving the male reproductive tract have been reported in the literature. We present here a case of bilateral epididymal sarcoidosis without radiographic evidence of intrathoracic lesion. A 46-year-old man presented with a one-week history of painless bilateral scrotal swellings. Physical examination detected multiple elastic firm nodules on both sides of the scrotum which showed no tenderness. The nodules seemed to involve the entire bilateral epididymides. Some irregularly shaped hypoechoic masses in the bilateral epididymides were identified on gray scale ultrasonography. On magnetic resonance images, the bilateral epididymides were seen to be enlarged, heterogeneous and nodular without any signs of testicular involvement. The lesion showed a slightly high signal intensity on the T2-weighted image. Pathological evaluation following bilateral epididymectomy found non-caseating epithelioid cell granulomas with giant cells in epididymal tissue, thus confirming a diagnosis of sarcoidosis. Gallium-67 scanning showed additional small hot spots in the anterior chest wall and extremities. Open biopsy of a superficial papular lesion in the dermis of the right upper arm was performed and pathological findings indicated sarcoid granulomas. This report also includes a review of the literature pertaining to sarcoidosis of the male reproductive tract.

Background : Although a correlation between microvessel density (MVD) and tumor aggressiveness has been established for several malignancies, the data for renal cell carcinoma (RCC) is conflicting. In order to clarify the significance of MVD, we investigated the relationships between MVD and tumor stage, grade, size, occurrence of metastasis and patient survival. Methods : Tumor specimens from 70 patients with primary renal cell carcinoma were examined by immunohistochemical staining for CD34.Results : There was a tendency for MVD to decrease from G1 to G3 tumors or from stage T1 to T3 tumors, although this was not statistically significant. However, the MVD for 56 non-metastatic and 14 metastatic tumors were significantly different ( P = 0.005) at 109 ± 67 and 58 ± 35 per ¥ 400 field (mean ± SD), respectively. Microvessel density for 36 large and 34 small tumors was also significantly different ( P < 0.0001) at 48 ± 22 and 142 ± 54 per ¥ 400 field, respectively. The survival rate of patients with small, low grade and hypervascular tumors was significantly higher than that of patients with large ( P = 0.0015), high grade ( P = 0.05) or low MVD ( P = 0.039) tumors. Cox proportional hazards regression analysis showed that tumor grade and size emerged as independent prognostic factors. Conclusion : High MVD in RCC was inversely associated with tumor aggressiveness, but MVD was not the independent prognostic factor.

BackgroundCytosine deaminase (CD) activates prodrug 5‐FC to 5‐FU and is used for suicide gene therapy (the CD/5‐FC system). E. coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that directly converts 5‐FU into 5‐fluorouridine monophosphate and improves the antitumoral effect of 5‐FU. This study demonstrates the effectiveness of transduction of the UPRT gene in addition to CD/5‐FC cancer suicide gene therapy.MethodsWe investigated a combined suicide gene transduction therapy for human hormone independent prostate cancer cell line DU145 using two separate adenovirus vectors expressing the E. coli CD and E. coli UPRT genes and systemic 5‐FC administration (the CD+UPRT/5‐FC system).ResultsCells transfected with AdCA‐UPRT showed approximately 57 times lower IC50 to 5‐FU compared with those transfected with AdCA‐LacZ. Furthermore, cells transfected with AdCA‐CD and AdCA‐UPRT proved to be more sensitive to 5‐FC compared with those transfected with AdCA‐CD. Intratumoral injection of AdCA‐CD and AdCA‐UPRT drastically suppressed the growth of tumors which had generated from DU145 cells inoculated into athymic (nude) mice compared with those injected with AdCA‐LacZ or AdCA‐LacZ and AdCA‐CD.ConclusionsThese results suggest that the CD+UPRT/5‐FC system could be a powerful factor in human prostate cancer suicide gene therapy. Copyright © 2002 John Wiley & Sons, Ltd.

Background : The 150-kDa oxygen-regulated protein ORP150, a new member of the heat shock protein family that functions as a molecular chaperone in the endoplasmic reticulum, was found to increase in infiltrating cancer cells. Since enhancement of ORP150 expression and the presence of vascular endothelial growth factor (VEGF) in human prostate cancer glands were immunohistochemically demonstrated, we examined whether transduced antisense ORP150 cDNA can reduce angiogenicity and tumorigenicity through suppression of VEGF secretion. Methods : Human prostate cancer specimens were immunohistochemically stained with fluorescein isothiocyanate (FITC) for ORP150 or vascular endothelial growth factor (VEGF). An adenovirus vector (Ad) carrying antisense ORP150 cDNA (AdCA-Antisense ORP150) was constructed and infected to prostate cancer DU145 cells. Expression of ORP150 in the cells was analyzed with western blotting and secretion of VEGF into the supernatant with an enzyme-linked immunoabsorbent assay (ELISA). Angiogenicity was evaluated by chorioallantoic membrane (CAM) assay. A nude mouse xenograft model was used to examine tumorigenicity. Results : Immunohistochemical study proved that the expression of ORP150 and VEGF was enhanced in the cytoplasm of prostate cancer cells. The Ad showed 100% transduction efficiency and minimum cytotoxicity when the cells were infected at a multiplicity of infection (MOI) of 20 for 24 h. Expression of ORP150 was substantially reduced by the antisense treatment. Secretion of VEGF into the culture supernatant was reduced to 30%. Consequently, the CAM assay showed relatively low angiogenicity, while marked suppression of tumor formation was observed in the xenograft model. Conclusion : Adenoviral-mediated antisense ORP150 cDNA transfer is well worth considering as an option for prostate cancer gene therapy.