Effects of new 17α-hydroxylase/C<subscript>17,20</subscript>-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo.
In: British Journal of Cancer, Jg. 81 (1999-10-15), Heft 4, S. 622-630
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Zugriff:
Our laboratory has been developing new inhibitors of a key regulatory enzyme of testicular and adrenal androgen synthesis 17α-(hydroxylase/C)17,20(-lyase (P450c17), with the aim of improving prostate cancer treatment. We designed and evaluated two groups of azolyl)steroids:D5-non-competitive inhibitors (Δ5NCIs), VN/63-1, VN/85-1, VN/87-1 and their corresponding Δ4 derivatives (Δ4NCIs), VN/107-1, VN/108-1 and VN/109-1. The human P450c17 gene was transfected into LNCaP human prostate cancer cells, and the resultant LNCaP-(CYP17 cells were utilized to evaluate the inhibitory potency of the new azolyl steroids. VN/85-1 and VN/108-1 had the lowest IC[SUB50] (values of) 1.25 ± 0.44 nM and 2.96 ± 0.78 nM respectively, which are much lower than that of the known P450 inhibitor ketoconazole (80.7 ± 1.8 nM). To determine whether the compounds had direct actions on proliferation of wild-type LNCaP cells, cell growth studies were performed. All of the Δ5NCIs and VN/108-1 blocked the growth-stimulating effects of androgens. In steroid-free media, the Δ5NCIs decreased the proliferation of LNCaP cells by 35-40%, while all of the Δ4NCIs stimulated LNCaP cells growth 1.5- to 2-fold. In androgen receptor (AR) binding studies, carried out to determine the mechanism of this effect, all of the Δ4NCIs (5 μM) displaced 77-82% of synthetic androgen R1881 (5 nM) from the LNCaP AR. The anti-androgen flutamide and the Δ5NCIs displaced 53% and 32-51% of R1881 bound to AR respectively. These results suggested that the Δ5NCIs may also be acting as anti-androgens. We further evaluated our inhibitors in male severe combined immuno-deficient mice bearing LNCaP tumour xenografts. In this model VN/85-1 was as effective as finasteride at inhibiting tumor growth (26% and 28% inhibition, respectively) and the inhibitory effect of VN/87-1 was similar to that of castration (33% and 36% inhibition respectively). These... [ABSTRACT FROM AUTHOR]
Titel: |
Effects of new 17α-hydroxylase/C<subscript>17,20</subscript>-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo.
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Autor/in / Beteiligte Person: | Grigoryev, D N ; Long, B J ; Nnane, I P ; Njar, V C O ; Liu, Y ; Brodie, A M H |
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Zeitschrift: | British Journal of Cancer, Jg. 81 (1999-10-15), Heft 4, S. 622-630 |
Veröffentlichung: | 1999 |
Medientyp: | academicJournal |
ISSN: | 0007-0920 (print) |
DOI: | 10.1038/sj.bjc.6690739 |
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