Prostate news article, December 2005
LONG
TERM CASODEX (BICALUTAMIDE) TREATMENT IN VITRO RESULTS IN
ALTERED ANDROGEN RECEPTOR MEDIATED SIGNALING IN PROSTATE
CANCER CELLS Visiting Professor to St George's Hospital, London |
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Experimental work published by Dr. Hobisch and colleagues from Feldkirch and Innsbruck, Austria as an electronic publication in The Prostate, investigates the long-term effect of Casodex (bicalutamide) on prostate cancer (CaP) cell biology.
Androgen-sensitive LNCaP cells were grown long-term in the presence of the synthetic androgen R1881 and the androgen-receptor inhibitor, bicalutamide (LNCaP-Bic). Once the LNCaP-Bic cell line was established, its proliferation in the presence of androgens, bicalutamide and the vitamin E derivative tocopherol succinate (TS) was assessed.
The studies sought to determine whether disruption of the androgen-signaling pathway is sufficient to prevent tumour growth and whether functional AR is required for the anti-proliferative effect of TS. LNCaP-Bic cells proliferated 3-fold faster than parental LNCaP cells when grown in steroid-depleted media, which did not change with the addition of either R1881 or bicalutamide. This suggests that acquisition of agonistic properties of bicalutamide in cells selected after continuous treatment with anti-androgens does not occur. The LNCaP-Bic cells loose dependency on exogenous androgen and bicalutamide then is also without effect.
The authors investigated whether there was up regulated AR expression or activity. In contrast to long-term androgen-deprived cells, the LNCaP-Bic cells showed no adaptation to low androgen conditions by increasing AR expression or transcriptional activity.
To investigate the role of AR in growth regulation of LNCaP-Bic cells, both LNCaP and LNCaP-Bic cells were pre-treated with TS followed by the addition of androgen. LNCaP cells demonstrated growth inhibition, but only minor inhibition of LNCaP-Bic cells was noted. AR and PSA expression were both down regulated by TS in both cell lines.
AR mediated signaling is not enhanced in cells selected in the presence
of the anti-androgen bicalutamide. This suggests that mechanisms
of tumour progression after bicalutamide treatment may differ from those
that emerge after chronic androgen deprivation. AR mediated
signaling may be different in these two circumstances and in patients treated
with long term anti-androgen therapy; tumour progression may be independent
of AR. Validation and extrapolation of these findings are important
prior to clinical translation but do suggest that patients whose PSa rises
in spite of treatment with Casodex may still respond to androgen deprivation
with an LHRH analogue such as Zoladex (goserelin).
Reference: Prostate 2005; epub.
31 12 2005