These results suggest that high expression of BMP-7 in metastatic bone lesions of prostate cancer is related to osteoblastic metastasis. BMP-7 in the bone metastasis tissue indicates that the cells expressing BMP-7 probably originated from the prostate, because we have detected high expression of BMP-7 in the prostate. Prostate 54: 268-274, 2003.

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Diethylstilbestrol (DES) is a synthetic oestrogen, and its anticancer effects are exerted in androgen-dependent prostate cancer. The administration of DES decreases serum testosterone to castration levels. However, in androgen-independent prostate cancer patients, who are already orchiectomised, the administration of DES improves symptoms and decreases prostate-specific antigen (PSA). The mechanisms responsible for these direct inhibitory effects have been explained as biological actions not mediated by oestrogen receptors. We assessed the gene expression profiles of prostate cancer cells treated with DES, and investigated direct inhibitory effects of DES. DES inhibited the proliferation of LNCaP and PC-3 cells. cDNA microarray analysis showed that expression of many genes was downregulated by DES. However, insulin-like growth factor binding protein 6 (IGFBP-6) gene expression levels were upregulated in PC-3 cells. IGFBP-6 gene expression and protein levels significantly increased after DES treatment. Recombinant IGFBP-6 inhibited cell proliferation, and the inhibitory effect of DES was neutralised by anti-IGFBP-6 antibody. From the immunohistochemical analysis of IGFBP-6 using biopsy samples from androgen-independent prostate cancer, we found IGFBP-6 expression in androgen independent prostate cancer, and that DES treatment increased the IGFBP-6 staining intensity of the cancer cells in one sample. These findings suggested that DES induces IGFBP-6, which inhibits cell proliferation in an androgen-independent prostate cancer cell line, PC-3. IGFBP-6 therefore might be involved in the direct effects of DES in androgen-independent prostate cancer. (Ferro et al, 1989), and diethylstilbestrol diphosphate (DESdP) is a nontoxic prodrug form of DES (Flocks et al, 1955;Abramson et al, 1982). The palliative effects of DESdP administered to advanced-, hormoneinsensitive prostate cancer patients are well known (Flocks et al, 1955;Colapinto et al, 1961;Band et al, 1973;Droz et al, 1994;Takezawa et al, 2001). DESdP relieves bone pain in the majority of patients with metastatic prostate cancer who receive therapy (Hawtrey et al, 1974;Takezawa et al, 2001).The administration of oestrogenic analogues causes the suppression of luteinising hormone-releasing-factor stimulation of the pituitary gland (Paulson, 1984). In addition, the subsequent reduction of testosterone synthesis induces anorchid levels of circulating serum testosterone (Paulson, 1984). The beneficial effect of DES therapy for previously orchiectomised patients, however, indicates that DES may not operate solely through the pituitary -gonadal axis. Several studies have sought to define the mode of DES action on a cellular level. DES treatment inhibits the growth of primary cultures derived from benign hyperplasia and prostate carcinoma samples (Brehmer et al, 1972) as well as prostate cancer cell lines (Schulz et al, 1990). Intracellular localisation studies of DES inhibition have targeted mitochondrial adenosine triphosphate synthase (McEnery et al, 1989), respir...

The effect of a synthetic steroidal anti‐androgen, TZP‐4238, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Old male beagle dogs (5–9 years old) were divided into three experimental groups. Group 1 consisted of BPH controls. Groups 2 and 3 received TZP‐4238 0.1 mg/kg/day and chlormadinone acetate (CMA) 0.3 mg/kg/day P.o., respectively, for 5 months. In group 1, glandular hyperplasia of the prostate was clearly detected. In contrast, TZP‐4238 (Group 2) or CMA (Group 3) produced marked atrophy of the glandular epithelium. In addition, a histopathological study showed that TZP‐4238 or CMA medication for 5 months exerted no effect on the testes and the pituitary luteinizing hormone (LH) cells. Therefore, it is suggested that TZP 4238 (0.1 mg/kg) or CMA (0.3 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes and pituitary LH cells. However, slightly decreased serum testosterone levels were found in TZP 4238 treated animals, due apparently to a direct and/or indirect effect on the testes. Thus, it is suggested that a marginal antigonadotrophic effect cannot be excluded. It is concluded that TZP‐4238 is a potent anti‐androgen for the treatment of spontaneous canine BPH, without any negative influence on the function of the testes and the pituitary LH cells. Acta Pathol Jpn 42: 151–157, 1992.

To clarify the effects of estrogen on the prostate of androgen-treated rats, we administered estradiol (E2; 0.01 mg/day) to testosterone (T; 1 mg/day)-treated Wistar rats under various conditions. There were three variable factors: the age of the rat, the untreated period after castration, and the presence of testes. Under all conditions, E2 stimulated the growth of the prostate in T-treated rats compared with growth in rats in treated with T only. To analyze the mechanism underlying this enhancement of prostate growth by estrogen, we measured 5-alpha-reductase activity and calculated its kinetic parameters, i.e., both Vmax and Km. The Vmax of the nuclear fraction was higher in E2-administered T-treated rats than in T only-treated rats. In contrast, the Vmax of the microsomal fraction was lower in E2-administered rats. Km values in the two groups showed no significant differences. Elevation of the nuclear fraction of 5-alpha-reductase activity could explain the synergistic effects of estrogen on the prostate growth of androgen-treated rats.