PubMed · 356569
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H R Ochs, D J Greenblatt, G Bodem, T W Smith. 1978. Spironolactone.. https://doi.org/10.1016/0002-8703(78)90052-2
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Androgens have significant beneficial effects on the skeleton. However, studies on the effects of androgens on osteoblasts are limited due to the absence of appropriate model systems that combine completeness of the osteoblastic phenotype, rapid proliferation rate, and stable expression of the androgen receptor (AR). Thus, we stably transfected the conditionally immortalized human fetal osteoblastic cell line (hFOB) with the human wild-type AR (hAR) cDNA. Compared to nontransfected hFOB cells, constitutive hAR mRNA expression in three independent hAR-transfected hFOB clones (hFOB/AR) was 15-fold higher in hFOB/AR-16, 62-fold higher in hFOB/AR-2, and 72-fold higher in hFOB/AR-6 cells, respectively, as assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Detectable constitutive levels of hAR mRNA by Northern blot analysis were present in hFOB/AR-2 and hFOB/AR-6 cells, but not in hFOB/AR-16 or hFOB cells, respectively. Treatment with 5 alpha-dihydrotestosterone (5 alpha-DHT) (10(-8) M) for 24 h did not alter hAR mRNA steady state levels in the hFOB/AR cell lines. Nuclear binding studies demonstrated 152 +/- 73 (mean +/- SEM) functional hARs/nucleus in non-transfected hFOB cells, 3,940 +/- 395 functional hARs/nucleus in hFOB/AR-2 cells, and 3,987 +/- 823 hARs/nucleus in hFOB/AR-6 cells, respectively. Treatment with 5 alpha-DHT increased the expression of a transiently transfected androgen response element-chloramphenicol acetyltransferase (ARE-CAT) reporter construct in hFOB/AR-6 cells in a dose- and time-dependent manner; no such effect was observed in transiently transfected hFOB cells lacking exogenously transfected hARs. Moreover, 5 alpha-DHT-induced ARE-CAT expression was inhibited by the selective androgen receptor antagonist, hydroxyflutamide. In summary, we have developed and characterized androgen-responsive osteoblastic cell lines derived from normal human fetal bone that express physiological levels of functional hARs. These cell lines should provide a suitable model for further studies on the effects of androgens on osteoblast function, including the identification of potential androgen-regulated growth factors and cytokines.
BACKGROUND: This study attempted to define unfavorable locoregional prostate carcinoma and presents the results of treatment with combined radiation and androgen ablation for these patients. METHODS: Of a group of 938 men with clinically localized N0/NX disease treated with radiation alone, an unfavorable category included all men with prostate specific antigen (PSA) > 20 ng/mL and all men with 10 < PSA < or = 20 ng/mL but with Gleason's grade > 7. One hundred and eighty-five such men treated with radiation alone and an additional 100 men with similar disease received radiation with early androgen ablation. A second cohort was comprised of 229 men with lymphadenectomy proven pelvic lymph node metastases, with 185 receiving early androgen ablation alone and 44 receiving androgen ablation and local radiation. The outcomes, with recurrence or rising PSA as the endpoint, were compared among these various treatment groups using multivariate techniques. RESULTS: Disease outcome with the combined modality treatment was dramatically improved in both cohorts of men. For those with unfavorable N0/NX disease, the failure rate at 5 years decreased from 82% with only radiation therapy to 15% with combined treatment. Likewise, for patients with lymph node disease, the failure rate at 5 years decreased from 58% with only androgen ablation to 10% with combined treatment. For the whole group with unfavorable disease (unfavorable N0/NX and lymph node positive disease) the 6-year failure decreased from 71% with single modality treatment to 13% with bimodality treatment. There was a close relationship between the incidence of lymph node disease and prognostic categories and patients with otherwise unfavorable disease did not have their poor outlook ameliorated by undergoing a negative lymphadenectomy. CONCLUSIONS: Unfavorable locoregional prostate carcinoma can be recognized on the basis of pretreatment PSA level, T category, and Gleason's grade without specific evaluation of pelvic lymph node status. Combined local radiation and androgen ablation for patients with unfavorable disease results in a substantial improvement in disease control compared with that achieved by either modality alone. The authors found no improvement in survival because all groups of men had a normal life expectancy to at least 5 years.