PubMed · 11022717
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T Kotake. 2000. [Bicalutamide].. https://pubmed.ncbi.nlm.nih.gov/11022717/
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During the last decade, the possible effects of xenobiotics on male reproductive health have resulted in great concern. More recently, evidence of antiandrogen effect in vivo by certain chemicals has been reported. The classical Hershberger in vivo assay determining organ weight changes can be improved by measuring hormone levels as well as determining changes in gene expression of androgen-responsive genes. A real-time RT-PCR method using LightCycler technology (Roche) suitable for quantitative determination of gene expression is described. The technique combines rapid thermocycling with online fluorescence detection of PCR product formation. In this study, investigation of expression of prostate specific binding protein polypeptide C3 (PBP C3) and testosterone-repressed prostatic message 2 (TRPM-2) in the ventral prostate was performed in 60-days-old castrated Wistar rats treated daily with testosterone with or without addition of flutamide or vinclozolin for 7 days in total. We show that we can quantify the level of gene expression by use of LightCycler technology, supported by changes in reproductive organ weights as well as in hormone levels, and that analysis of gene expression levels is an even more sensitive endpoint.
Caveolin-1 is an integral protein of caveolae, known to play important roles in signal transduction and lipid transport. We demonstrate that caveolin-1 expression is significantly increased in primary and metastatic human prostate cancer after androgen ablation therapy. We also show that caveolin-1 is secreted by androgen-insensitive prostate cancer cells, and that this secretion is regulated by steroid hormones. Significantly, caveolin-1 was detected in the MDL(3) fraction of serum specimens from patients with advanced prostate cancer and to a lesser extent in normal subjects. Conditioned media from high passage caveolin-1 secreting, androgen-insensitive, LNCaP cells stimulated increased viability and clonal growth of low passage, caveolin-1-negative, androgen-sensitive, LNCaP cells in vitro, and this effect was blocked by treating the media with caveolin-1 antibody. i.p. injections of caveolin-1 antibody suppressed the orthotopic growth and spontaneous metastasis of highly metastatic, androgen-insensitive caveolin-1-secreting mouse prostate cancer. Overall, our results establish caveolin-1 as an autocrine/paracrine factor that is associated with androgen-insensitive prostate cancer. We demonstrate the potential for caveolin-1 as a therapeutic target for this important malignancy.
A series of arylhydantoin derivatives modeled after the antiandrogen RU 58841 was generated to identify potential candidates for development as androgen receptor (AR) radioligands. Side-chain modified derivatives of RU 58841, suitable for labeling with either carbon-11 or radiohalogens (fluorine-18, iodine-123), were synthesized and tested for their AR binding affinities. The N-(iodopropenyl) derivative 13 (Ki = 13 nM) is a potential candidate for development as a radioiodinated AR ligand.