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M J Campbell, E Elstner, S Holden, M Uskokovic and H P Koeffler

ABSTRACT

We have synthesized and studied the ability of a series of seven novel 1α,25(OH)2 vitamin D3 analogues to inhibit clonal growth of prostate cancer cells (LNCaP, PC-3 and DU-145). Addition of double and triple bonds to the C/D ring (C-16) and side chain (C-22 and C-23) as well as lengthening of the side chain were important for enhanced activity against LNCaP and PC-3. Reorientation of the side chain in the 20-epi configuration resulted in analogues that were extremely potent only against LNCaP (ED50 ≈ 5 × 10−11 m). Compounds with six fluorines on the end of the side chain were very active against both PC-3 and LNCaP (ED50 ≈ 2 × 10−8 m). DU-145 cells were relatively resistant to compounds with all of these modifications, but removal of C-19 (e.g. 1,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3) resulted in an analogue that was inhibitory against all three prostate cell lines. Further analysis showed that pulse exposure (3 days, 10−7 m) to this analogue was enough to inhibit clonal growth of PC-3 cells by 50%. The same exposure also induced cell cycle arrest of all three cell lines, accompanied by upregulated protein expression of the cyclin-dependent kinase inhibitor (CDKI) known as p21waf1 in all three cell lines, and the CDKI known as p27kip1 in LNCaP cells. Associated with upregulation of these CDKIs, partial differentiation occurred as measured by increased expression of both prostate-specific antigen by LNCaP cells and E-cadherin, a cell adhesion protein that may act as a putative tumour suppressor (LNCaP and PC-3 cells). In summary, this is the first report of a potent series of 19-nor-vitamin D3 analogues with the ability to inhibit proliferation of LNCaP, PC-3 and DU-145 prostate cancer cell lines. These compounds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.

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F. Claessens, L. Dirckx, B. Delaey, J.-L. Decourt, K. Hemschoote, B. Peeters and W. Rombauts

ABSTRACT

The complete gene encoding the polypeptide Cl of the complex androgen-controlled prostatic binding protein was isolated from a rat genomic library. A new genomic fragment (C2B) containing only the 5′ part of a C2-related gene was also purified. The segments containing exon 1 and a large part of the adjacent sequences were analysed and compared with the corresponding region of the C2A gene which has been completely sequenced previously. The high structural similarity extending over a large part of all three genomic fragments suggests the duplication of a common ancestral gene, followed by a more recent duplication of the C2-coding region. However, since the structural similarity upstream of position − 150 between C2A and C2B abruptly disappears and no transcripts specific for the C2B region can be detected in prostate RNA, we propose that at a later stage in evolution the C2B region was disrupted and inactivated. Despite the common origin and the similar regulation of the two active genes, Cl and C2A, the only obvious conserved structural element is the homopurine stretch located at position −400, although sequence motifs resembling steroid hormone response elements are present at several locations.

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Nick Makridakis and Juergen K V Reichardt

Introduction The prostate gland depends on androgens for both its growth and development ( Cheng et al. 1993 ). We have reported evidence that increased intraprostatic androgen metabolism, particularly through genetic variants of

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S Kerkhofs, S Denayer, A Haelens and F Claessens

differentiation of male urogenital structures (male external genitalia, urethra, and prostate; Wilson et al . 1993 , Nef & Parada 2000 ). To mediate their actions, testosterone, and DHT bind to the intracellular androgen receptor (AR), a ligand

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Karine Steketee, Angelique C J Ziel-van der Made, Hetty A G M van der Korput, Adriaan B Houtsmuller and Jan Trapman

activity of several promoters can be regulated by more than one of these receptors. Examples are the MMTV promoter, and the promoters of the C3 , the cystatin-related protein (CRP) and the prostate specific antigen ( PSA) gene ( Ham et al. 1988

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G Pelletier, V Luu-The, S Li, L Ren and F Labrie

et al. 1992 , Lin et al. 1992 ). An analysis of the tissue distribution revealed the expression of 17β-HSD type 1 mRNA in steroidogenic as well as various other peripheral tissues, including the placenta, ovary, breast, endometrium, prostate, skin

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F M Fioretti, A Sita-Lumsden, C L Bevan and G N Brooke

measure of receptor activity. Prostate-specific antigen (PSA) is an androgen-responsive gene, serum levels of the protein product of which are used as a biomarker for the management of prostate cancer. Although generally regarded as a prostate

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Andrew P Trotta, Eleanor F Need, Lisa M Butler, Luke A Selth, Melissa A O'Loughlin, Gerhard A Coetzee, Wayne D Tilley and Grant Buchanan

be indicative of an altered status of receptor activation or response. This is most commonly observed in prostate cancer following the failure of androgen deprivation therapy, whereby the AR subcellular distribution shifts to become predominately

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Ikuhiro Maeda, Toru Takano, Hiroshi Yoshida, Fumio Matsuzuka, Nobuyuki Amino and Akira Miyauchi

blood cells (WBC) and prostate were analyzed. The following primers were used for the PCR: one was 5SN1SC (0.5 μM): 5′-TTCCTGTCCCACAACTTTC TCACG-3′ (base 3202–3225 of tensin3 cDNA (GenBank AF417489)), and the other was 3SN1SC (0.5 μM): 5

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V X Jin, H Sun, T T Pohar, S Liyanarachchi, S K Palaniswamy, T H-M Huang and R V Davuluri

Introduction The estrogen receptors (ER) α and β are steroid hormone receptors that play important roles in the normal development of various organs, such as the brain, heart, bone, breast, uterus and prostate. Malignancy of the ER