BACKGROUND.Clinically, the lethal phenotypes of human prostate cancer are characterized by their progression to androgen-independence and their propensity to form osseous metastases. We reported previously on the establishment of androgen-independent (AI) human prostate cancer cell lines derived from androgen-dependent (AD) LNCaP cells, with androgen independence defined as the capability of prostate cancer cells to grow in castrated hosts. One of the sublines, C4-2, was found to be AI, highly tumorigenic, and metastatic, having a proclivity for metastasis to the bone. METHODS. We established the AI and bone metastatic cell sublines B2, B3, B4, and B5 from the parental C4-2 subline, using a previously established coinoculating procedure. We determined the biologic behavior of the parental and derivative LNCaP sublines in vivo and in vitro, as well as their molecular and cytogenetic characteristics. RESULTS. Unlike other human prostate cancer models, the LNCaP progression model shares remarkable similarities with human prostate cancer. We observed a comparable pattern of metastasis from the primary to the lymph node and to the axial skeleton, with a predominant phenotype of osteoblastic reaction; 25-37.5% of the animals developed paraplegia. Cytogenetic and biochemical characterizations of LNCaP sublines also indicate close similarities between human prostate cancer and the LNCaP progression model. Additional chromosomal changes were detected in B2-B5 sublines derived from C4-2 bone metastases. These LNCaP sublines were found to grow faster under anchorage-dependent but not -independent conditions. The in vitro invasion and in vivo metastatic potential of these LNCaP sublines surprisingly correlated with anchorage-dependent and not -independent growth. The derivative LNCaP sublines when cultured in vitro produced a substantially higher (20-30-fold) amount of basal steady-state concentrations of PSA than that of the parental LNCaP cells. PSA production was high initially, but was markedly reduced when the derivative cell lines were inoculated and allowed to grow long-term in vivo for the establishment of tumors and metastasis, suggesting that unknown host factors derived either from the prostate or the bone can effectively downregulate PSA expression by prostate tumor epithelium. CONCLUSIONS. The LNCaP model of human prostate cancer progression will help improve our understanding of the mechanisms of androgen-independence and osseous metastasis, and tumor-host determinants of PSA expression.

LNCaP lineage‐derived human prostate cancer cell lines C4‐2 and C4‐2B4 acquire androgen independence and osseous metastatic potential in vivo. Using C4‐2 and C4‐2B4 the goals of the current investigation were 1) to establish an ideal bone xenograft model for prostate cancer cells in intact athymic or SCID/bg mice using an intraosseous route of tumor cell administration and 2) to compare prostate cancer metastasis by administering cells either through intravenous (i.v.) or intracardiac administration in athymic or SCID/bg mice. Subsequent to tumor cell administration, prostate cancer growth in the skeleton was assessed by radiographic bone density, serum prostate‐specific antigen (PSA) levels, presence of hematogenous prostate cancer cells and histopathologic evaluation of tumor specimens in the lymph node and skeleton. Our results show that whereas LNCaP cells injected intracardially failed to develop metastasis, C4‐2 cells injected similarly had the highest metastatic capability in SCID/bg mice. Retroperitoneal and mediastinal lymph node metastases were noted in 3/7 animals, whereas 2/7 animals developed osteoblastic spine metastases. Intracardiac injection of C4‐2 in athymic hosts produced spinal metastases in 1/5 animals at 8–12 weeks post‐injection; PC‐3 injected intracardially also metastasized to the bone but yielded osteolytic responses. Intravenous injection of either LNCaP or C4‐2 failed to establish tumor colonies. Intrailiac injection of C4‐2 but not LNCaP nor C4‐2B4 cells in athymic mice established rapidly growing tumors in 4/8 animals at 2–7 weeks after inoculation. Intrafemoral injection of C4‐2 (9/16) and C4‐2B4 (5/18) but not LNCaP (0/13) cells resulted in the development of osteoblastic bone lesions in athymic mice (mean: 6 weeks, range: 3–12 weeks). In SCID/bg mice, intrafemoral injection of LNCaP (6/8), C4‐2 (8/8) and C4‐2B4 (8/8) cells formed PSA‐producing, osteoblastic tumors in the bone marrow space within 3–5 weeks after tumor cell inoculation. A stepwise increase of serum PSA was detected in all animals. Reverse transcription‐polymerase chain reaction (RT‐PCR) to detect hematogenously disseminated prostate cancer cells could not be correlated to either serum PSA level or histological evidence of tumor cells in the marrow space. We have thus established a PSA‐producing and osteoblastic human prostate cancer xenograft model in mice. Int. J. Cancer 77:887–894, 1998.© 1998 Wiley‐Liss, Inc.

BACKGROUND Clinically, the lethal phenotypes of human prostate cancer are characterized by their progression to androgen‐independence and their propensity to form osseous metastases. We reported previously on the establishment of androgen‐independent (AI) human prostate cancer cell lines derived from androgen‐dependent (AD) LNCaP cells, with androgen independence defined as the capability of prostate cancer cells to grow in castrated hosts. One of the sublines, C4‐2, was found to be AI, highly tumorigenic, and metastatic, having a proclivity for metastasis to the bone. METHODS We established the AI and bone metastatic cell sublines B2, B3, B4, and B5 from the parental C4‐2 subline, using a previously established coinoculating procedure. We determined the biologic behavior of the parental and derivative LNCaP sublines in vivo and in vitro, as well as their molecular and cytogenetic characteristics. RESULTS Unlike other human prostate cancer models, the LNCaP progression model shares remarkable similarities with human prostate cancer. We observed a comparable pattern of metastasis from the primary to the lymph node and to the axial skeleton, with a predominant phenotype of osteoblastic reaction; 25–37.5% of the animals developed paraplegia. Cytogenetic and biochemical characterizations of LNCaP sublines also indicate close similarities between human prostate cancer and the LNCaP progression model. Additional chromosomal changes were detected in B2–B5 sublines derived from C4‐2 bone metastases. These LNCaP sublines were found to grow faster under anchorage‐dependent but not ‐independent conditions. The in vitro invasion and in vivo metastatic potential of these LNCaP sublines surprisingly correlated with anchorage‐dependent and not ‐independent growth. The derivative LNCaP sublines when cultured in vitro produced a substantially higher (20–30‐fold) amount of basal steady‐state concentrations of PSA than that of the parental LNCaP cells. PSA production was high initially, but was markedly reduced when the derivative cell lines were inoculated and allowed to grow long‐term in vivo for the establishment of tumors and metastasis, suggesting that unknown host factors derived either from the prostate or the bone can effectively downregulate PSA expression by prostate tumor epithelium. CONCLUSIONS The LNCaP model of human prostate cancer progression will help improve our understanding of the mechanisms of androgen‐independence and osseous metastasis, and tumor‐host determinants of PSA expression. Prostate 44:91–103, 2000. © 2000 Wiley‐Liss, Inc.

Introduction Female sexual function contains four major subtypes of desire, arousal, orgasm, and pain. Few studies used validated instruments to determine the dysfunction in these areas and assess their risk factors. Aim To assess the prevalence of and risk factors for individual components of sexual difficulty in women. Methods A self-administered questionnaire containing the Female Sexual Function Index (FSFI) was given to 2,159 woman employees of two hospitals to assess their sexual function and its correlates. Main Outcome Measures The associations between female sexual difficulty in individual domains defined by the FSFI domain scores and potential risk factors assessed by simple questions. Results Among the 1,580 respondents, 930 women’s data were eligible for analysis with a mean age of 36.1 years (range 20–67). Of them, 43.8% had sexual difficulty in one or more domains, including low desire in 31.3%; low arousal, 18.2%; low lubrication, 4.8%; low orgasmic function, 10.4%; low satisfaction, 7.3%; and sexual pain, 10.5%. Compared with the younger women (20–49 years), the oldest age group (50–67 years) had a significantly higher prevalence in low desire, low arousal, and low lubrication, but not in the other domains. Based on multivariate logistic regression analyses, poor relationship with the partner and perception of partner’s sexual dysfunction were major risk factors for low desire, low arousal, low orgasmic function, and low satisfaction. Age and urge urinary incontinence were associated with low lubrication and sexual pain. Most comorbidities were not related to these difficulties, except diabetes being related to low desire. Conclusions Relationship factors had substantial impact on female sexual function in desire, arousal, orgasm, and satisfaction. On the other hand, women’s lubrication problem and sexual pain were related predominantly with biological factors. These are initial results and future research is needed to confirm them.

What's known on the subject? and What does the study add?Silodosin administered by 4 mg twice daily is as effective as tamsulosin 0.2 mg daily in treating patients with LUTS associated with BPH.Relative to tamsulosin, silodosin has less cardiovascular side effects as judged by the minimal changes of blood pressure and pulse rats after treatment. OBJECTIVE• To test the hypothesis that the efficacy of silodosin would not be inferior to tamsulosin in treating patients with lower urinary tract symptoms associated with benign prostate hyperplasia (BPH). PATIENTS AND METHODS• At nine medical centres, 209 patients with an International Prostate Symptom Score (IPSS) of ≥ 13 were randomized to silodosin (4 mg twice daily) or tamsulosin (0.2 mg once daily) for 12 weeks.• The primary efficacy measure was the mean change from baseline to endpoint in IPSS.• The non-inferiority margin of the IPSS change was set at 1.0.• Secondary efficacy measures included change in maximal urinary flow rate (Q max ) and health-related quality of life (HRQL) score. RESULTS• Of the 170 (81.3%) patients who completed the study, 86.2% in the silodosin group vs 81.9% in the tamsulosin group achieved a ≥ 25% decrease in IPSS ( P = 0.53).• The mean difference (silodosin minus tamsulosin) in IPSS change from baseline was − 0.60 (95% confidence interval − 2.15, 0.95), inferring the non-inferiority of silodosin to tamsulosin.• The mean changes in the Q max and HRQL score from baseline were comparable between the groups (both, P > 0.05). Although patients receiving silodosin had a significantly higher incidence of abnormal ejaculation (9.7% vs tamsulosin 1.0%, P = 0.009), only 1.9% discontinued treatment.• Tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure ( − 4.2 mmHg, within-group P = 0.004) relative to the negligible change of silodosin ( − 0.1 mmHg, within-group P = 0.96) CONCLUSION• The trial shows the non-inferiority of silodosin 4 mg twice daily to tamsulosin 0.2 mg once daily in patients with symptoms of BPH.