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Study shows additional role for abiraterone in blocking tumor growth in CRPC
Date:3/15/2013

terone are converted to androgens via CYP17A1 enzymatic activity) in CRPC patients has demonstrated a prolonged survival, but may eventually fail because androgen precursors can activate the AR directly," explained Moll.

In their study, the researchers generated castration resistant clones by long-term culture of VCaP and DuCaP cell lines in steroid-stripped medium (DCC), with or without addition of anti-androgens used in the clinic. Experiments were conducted with a subset of AR-overexpressing CRPC clones to test cell growth and AR-activation in the presence of adrenal androgen precursors, pregnenolone and progesterone or dihydrotestosterone in combinations with increasing levels of abiraterone.

The results showed that high (100 nM) levels of progesterone, but not of pregnenolone, induced cell growth in VCaP and DuCaP CRPC clones, which could not be blocked by low levels of abiraterone (0,1 M) that are known to fully inhibit CYP17A1 activity (and thus potential subsequent testosterone production).

In a second experiment, the researchers showed that high levels of precursor androgens can directly activate the AR using a model with a fluorescent AR and that ligand-induced AR-translocation from the cytoplasm to the nucleus was slowed down by abiraterone.

"However, high levels of abiraterone (>5 mM) inhibited steroid-induced, but not basal growth of these (CRPC) cells. This finding, together with the observation that DHT-induced growth was inhibited by high levels of abiraterone, indicates that abiraterone can act as an anti-androgen," the researchers wrote.

"We show that abiraterone, a CYP17A1-blocking drug that has recently been approved in the treatment of CRPC, possesses an additional antiandrogenic property and can block androgen precursor-induced AR-activation at higher concentrations than what is needed for CYP17A1 specific inhibition. This may be a good argument to increase abiraterone exposure in the treatment of C
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Contact: Ivanka Moerkerken
i.moerkerken@uroweb.org
31-026-389-0680
European Association of Urology
Source:Eurekalert

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