Author: Elsasser-Beile, Ursula ; Gierschner, Dorothee ; Wetterauer, Ulrich ; Buhler, Patrick ; Wolf, Philipp ; Fischer, Thomas ; Schultze-Seemann, Wolfgang

Introduction: Androgen deprivation is the preferred treatment for disseminated prostate cancer. However, it mostly leads to the development of incurable androgen-independent disease. The aim of the present study was to compare gene expression changes that occur after treatment with either the antiandrogen bicalutamide or the 5-α-reductase inhibitors finasteride (MK906) and MK386. Materials and Methods: LNCaP cells of low passages were treated with MK906 and MK386 at 5 µM each or with bicalutamide at 10 µM for 48 h. In these cultures we analyzed the expression of 22,500 transcripts on the Affymetrix Human U133+ 2.0 GeneChip platform. Gene expression was verified by real-time quantitative Taqman PCR. Results: Our studies revealed 312 differentially regulated genes upon bicalutamide treatment and 68 differentially regulated genes upon treatment with the 5-α-reductase inhibitors. There were 35 genes equally regulated by both drugs. This subset of genes included those with the highest fold change in both treatment groups. In the subset KlK2, TMPRSS2, TRGC2, PMEPA1 and TM4SF1 were downregulated, whereas EGR1, DDC and OPRK1 were upregulated. Conclusions: A cohort of interesting genes that are differentially expressed after androgen withdrawal could be found in this study. Investigation into these genes could contribute to a better understanding of antiandrogen treatment and development of androgen-independent prostate cancer.

01 Jul 2008·Journal of UrologyQ1 · MEDICINE

Effects of Dutasteride on Prostate Carcinoma Primary Cultures: A Comparative Study With Finasteride and MK386

Q1 · MEDICINE

Article

Author: Angelucci, Adriano ; Vicentini, Carlo ; Pomante, Roberto ; Muzi, Paola ; Bologna, Mauro ; Gravina, Giovanni Luca ; Festuccia, Claudio

PURPOSEThe profound decrease in serum dihydrotestosterone observed with the dual 5alpha-reductase inhibitor dutasteride makes it an attractive agent for prostate cancer therapy. To our knowledge we compared for the first time the antitumor effect of dutasteride with that of the specific 5alpha-reductase-1 inhibitor MK386 and the specific 5alpha-reductase-2 inhibitor finasteride in human prostate primary cultures.MATERIALS AND METHODSBiochemical markers of the cellular response to 5alpha-reductase inhibitors were evaluated in primary cultures of prostate epithelial cancer cells from 54 patients with prostate carcinoma.RESULTSIn our cohort of 54 patients prostate cancer cell growth decreased with dutasteride in 42 (about 78%), whereas in 21 (39%) it decreased with finasteride or MK386 alone. We observed a relationship between the levels of 5alpha-reductase enzymes in cell culture extracts and those revealed by immunohistochemistry in sections of samples from which we established primary cultures. Finasteride effects depended on 5alpha-reductase-2 levels and they were higher when the 5alpha-reductase-1:2 ratio was low. However, dutasteride effects were related to 5alpha-reductase-1 and 2 levels, and were not influenced by the 5alpha-reductase-1:2 ratio. Conversely the effects of MK386 were related to 5alpha-reductase-1 levels and they were higher when the 5alpha-reductase-1:2 ratio was high.CONCLUSIONSOur data may provide a rationale for the use of a dual 5alpha-reductase inhibitor rather than a mono specific inhibitor for the prevention or treatment of early prostate cancer. This finding appears to confirm some preliminary clinical results and it could be due to the simultaneous presence of each 5alpha-reductase isoenzyme in prostate tumor cells.

01 Apr 2008·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Different patterns of 5α-reductase expression, cellular distribution, and testosterone metabolism in human follicular dermal papilla cells

Q3 · BIOLOGY

Article

Author: Shicheng Liu ; Hitoshi Yamauchi

Androgens regulate hair growth, and 5alpha-reductase (5alphaR) plays a pivotal role in the action of androgens on target organs. To clarify the molecular mechanisms responsible for controlling hair growth, the present study presents evidence that the human follicular dermal papilla cells (DPCs) from either beard (bDPCs) or scalp hair (sDPCs) possess endogenous 5alphaR activity. Real-time RT-PCR revealed that the highest level of 5alphaR1 mRNA was found in bDPCs, followed by sDPCs, and a low but detectable level of 5alphaR1 mRNA was observed in fibroblasts. Minimally detectable levels of 5alphaR2 mRNA were found in all three cell types. A weak band at 26kDa corresponding to the human 5alphaR1 protein was detected by Western blot in both DPCs, but not in fibroblasts. Immuonofluorescence analysis confirmed that 5alphaR1 was localized to the cytoplasm rather than in the nuclei in both DPCs Furthermore, a 5alphaR assay using [(14)C]testosterone labeling in intact cells revealed that testosterone was transformed primarily into androstenedione, and in small amounts, into DHT. Our results demonstrate that the 5alphaR activities of either bDPCs or sDPCs are stronger than that of dermal fibroblasts, despite the fact that the major steroidogenic activity is attributed to 17beta-HSD rather than 5alphaR among the three cell types. The 5alphaR1 inhibitor MK386 exhibited a more potent inhibitory effect on 5alphaR activity than finasteride (5alphaR2 inhibitor) in bDPCs.

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Indication	Highest Phase	Country/Location	Organization	Date
Acne Vulgaris	Phase 2	United States	Merck GmbH	-
Acne Vulgaris	Phase 2	United States	Merck GmbH	-
Acne Vulgaris	Phase 2	-	Merck Sharp & Dohme Corp.	-
Acne Vulgaris	Phase 2	-	Merck Sharp & Dohme Corp.	-
Alopecia	Phase 2	-	Merck Sharp & Dohme Corp.	-
Alopecia	Phase 2	-	Merck Sharp & Dohme Corp.	-
Alopecia	Phase 2	United States	Merck GmbH	-
Alopecia	Phase 2	United States	Merck GmbH	-
Prostatic Cancer	Phase 2	United States	Merck & Co., Inc.	-
Prostatic Hyperplasia	Phase 2	United States	Merck GmbH	-

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