Purpose. Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence.Experimental Design. Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay.Results. Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 ؎ SD 0.115 and percentage positive nuclei, 83.7 ؎ 11.6) was similar to benign prostate (mean optical density, 0.315 ؎ 0.044 and percentage positive nuclei, 77.3 ؎ 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 ؎ 2.34 pmol/g tissue) and benign prostate (3.26 ؎ 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P ؍ 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgenregulated gene product, prostate-specific antigen, at 8.80 ؎ 10.80 nmol/g tissue.Conclusions. Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.
The immunocytochemical localization of neurons containing the 41 amino acid peptide corticotropin-releasing factor (CRF) in the rat brain is described. The detection of CRF-like immunoreactivity in neurons was facilitated by colchicine pretreatment of the rats and by silver intensification of the diaminobenzidine end-product. The presence of immunoreactive CRF in perikarya, neuronal processes, and terminals in all major subdivisions of the rat brain is demonstrated. Aggregates of CRF-immunoreactive perikarya are found in the paraventricular, supraoptic, medial and periventricular preoptic, and premammillary nuclei of the hypothalamus, the bed nuclei of the stria terminalis and of the anterior commissure, the medial septal nucleus, the nucleus accumbens, the central amygdaloid nucleus, the olfactory bulb, the locus ceruleus, the parabrachial nucleus, the superior and inferior colliculus, and the medial vestibular nucleus. A few scattered perikarya with CRF-like immunoreactivity are present along the paraventriculo-infundibular pathway, in the anterior hypothalamus, the cerebral cortex, the hippocampus, and the periaqueductal gray of the mesencephalon and pons. Processes with CRF-like immunoreactivity are present in all of the above areas as well as in the cerebellum. The densest accumulation of CRF-immunoreactive terminals is seen in the external zone of the median eminence, with some immunoreactive CRF also present in the internal zone. The widespread but selective distribution of neurons containing CRF-like immunoreactivity supports the neuroendocrine role of this peptide and suggests that CRF, similarly to other neuropeptides, may also function as a neuromodulator throughout the brain.
A protein designated acidic epididymal glycoprotein (AEG) was purified from rat epididymis using ion exchange chromatography on DEAE‐Sephadex, gel filtration in Sephadex G‐75 and affinity chromatography on Concanavalin‐A Sepharose. AEG is a major secretory product of the epididymis making up 2–3 per cent of total soluble protein. Antibody to AEG was raised in rabbits and purified by affinity chromatography on AEG‐Sepharose. Quantitation of AEG in cytosol using “rocket” immunoelectrophoresis showed AEG to increase in epididymal segments from caput to cauda. Ligation of the midcorpus decreased AEG in the cauda. Localization of AEG using an immunoperoxidase method revealed that it is secreted largely by the epithelium of caput and corpus beginning with the region distal to the initial segment. It appears to be secreted by a specific cell type, probably the so‐called “principal” cell. Specific staining of AEG was also noted in “clear” cells in the cauda. Spermatozoa become coated with AEG as they leave the initial segment and remain so during passage through the cauda.
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