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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
1999-9-28
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pubmed:abstractText |
Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the nonsteroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-1510931,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-1708363,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-2260966,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-2386943,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-2710689,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-2734981,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-3126493,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-3263955,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-447482,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-6273878,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-631930,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-6584201,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-6831420,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9111707,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9199369,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9215398,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9368054,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9565586,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9636157,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9658399,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10496349-9751496
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Androgen Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Androgen Receptor Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Androgens,
http://linkedlifedata.com/resource/pubmed/chemical/Anilides,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Nitriles,
http://linkedlifedata.com/resource/pubmed/chemical/Prostate-Specific Antigen,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Androgen,
http://linkedlifedata.com/resource/pubmed/chemical/Tosyl Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/bicalutamide
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0007-0920
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pubmed:author |
pubmed-author:BartschGG,
pubmed-author:CuligZZ,
pubmed-author:EderI EIE,
pubmed-author:ErdelMM,
pubmed-author:HittmairAA,
pubmed-author:HobischAA,
pubmed-author:HoffmannJJ,
pubmed-author:KlockerHH,
pubmed-author:ParczykKK,
pubmed-author:SchneiderM RMR,
pubmed-author:UtermannGG
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pubmed:issnType |
Print
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pubmed:volume |
81
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
242-51
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
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