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Inhibition of LNCaP prostate tumor growth in vivo by an antisense oligonucleotide directed against the human androgen receptor

Cancer Gene Therapy volume 9, pages 117–125 (2002)Cite this article

A Corrigendum to this article was published on 10 October 2007

Abstract

We have shown recently that a 15-mer phosphorothioate oligodeoxynucleotide (ODNas750/15) that hybridizes to the (CAG)n polyglutamine region of mRNA encoding human androgen receptor (AR) inhibits the expression of AR in LNCaP prostate cancer cells in vitro. This AR downregulation was accompanied by significant cell growth inhibition and reduced PSA secretion. In the present study we investigated the effects of this antisense AR ODN on prostate tumor growth in vivo using a mouse xenograft model. Via subcutaneously implanted diffusion pumps, either ODNas750/15 or a scrambled control sequence ODNsr750/15 was continuously administered into LNCaP tumor–bearing male nude mice for 7 weeks. Compared with untreated control animals, treatment with ODNas750/15 resulted in significant tumor growth inhibition. Retardation of tumor growth was also significant in castrated mice, whereas the scrambled control ODN did not exert any effects. No side effects such as loss of body weight were observed at any time of treatment. ODN treatment was well tolerated and, in contrast to castration, did not induce shrinkage of mouse prostates. Both AR expression in the tumor and PSA levels in mouse serum correlated with tumor size. However, we failed to demonstrate a correlation between tumor retardation and Ki-67 antigen expression and the number of apoptotic cells, respectively. Testing of antisense-treated LNCaP cells revealed that expression levels of other proteins that contain shorter polyglutamine sequence stretches such as HDAC2, TFIID, and c-jun were not affected. The present study demonstrates that downregulation of AR with antisense ODNas750/15 causes prostate tumor growth inhibition. These results further point out the important role of the AR in prostate tumors and support further testing of AR downregulation for treatment of prostate cancer.

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Acknowledgements

Financial support from Schering AG, Berlin, Germany and the Austrian Research Foundation (FWF SFB 002F203) are gratefully acknowledged. The authors thank G Hölzl, U Plawenn-Salvini, and A Tögel for excellent technical assistance.

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Authors and Affiliations

  1. Department of Urology, University of Innsbruck, Innsbruck, A-6020, Austria

    Iris E Eder, Georg Bartsch & Helmut Klocker

  2. Department of Experimental Oncology, Schering AG, Berlin, Germany

    Jens Hoffmann & Dieter Zopf

  3. Department of Pathology, University of Innsbruck, Innsbruck, A-6020, Austria

    Hermann Rogatsch & Georg Schäfer

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  1. Iris E Eder
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  2. Jens Hoffmann
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Correspondence to Helmut Klocker.

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Eder, I., Hoffmann, J., Rogatsch, H. et al. Inhibition of LNCaP prostate tumor growth in vivo by an antisense oligonucleotide directed against the human androgen receptor. Cancer Gene Ther 9, 117–125 (2002). https://doi.org/10.1038/sj.cgt.7700416

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