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Testosterone boosts for treatment of castration resistant prostate cancer: An experimental implementation of intermittent androgen deprivation
Author(s) -
Thelen Paul,
Heinrich Elmar,
Bremmer Felix,
Trojan Lutz,
Strauss Arne
Publication year - 2013
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22711
Subject(s) - prostate cancer , androgen receptor , testosterone (patch) , androgen , cancer research , endocrinology , medicine , androgen deprivation therapy , prostate , downregulation and upregulation , biology , cancer , hormone , biochemistry , gene
BACKGROUND The primary therapeutic target for non‐organ‐confined prostate cancer is the androgen receptor (AR). Main strategies to ablate AR function are androgen depletion and direct receptor blockade by AR antagonists. However, incurable castration resistant prostate cancer (CRPC) develops resistance mechanisms to cope with trace amounts of androgen including AR overexpression and mutation in the AR ligand binding domain. METHODS The CRPC cell model VCaP derivative of a prostate cancer bone metastasis was used in vitro and in nude mice in vivo to examine the effects of immediate testosterone boost on CRPC cells. In addition, a testosterone tolerant cell model was established by incremental acclimatization of VCaP cells to 1 nM testosterone. The effects of androgen withdrawal and testosterone boosts on gene expression were assessed by quantitative real‐time polymerase chain reaction, ELISA, and Western blots. Tumor cell proliferation was evaluated with a BrdU test. RESULTS Testosterone boosts on CRPC VCaP cells eliminate tumor cells to a higher extent than androgen withdrawal in androgen tolerant cells. The pronounced decrease of tumor cell proliferation was accompanied by a marked downregulation of AR expression regarding full‐length AR and splice variant AR V7. CONCLUSIONS Acquiring castration resistance of prostate cancer cells by AR overexpression and amplification obviously sensitizes such cells to testosterone concentrations as low as physiological values. This introduces novel therapeutic means to treat CRPC with non‐toxic measures and may find clinical implementation in intermittent androgen deprivation regimens. Prostate 73: 1699–1709, 2013 . © 2013 Wiley Periodicals, Inc.