Currently available methods for treatment of human prostatic carcinoma aim to inactivate the androgen receptor (AR) by androgen deprivation or blockade with anti-androgens. Failure of endocrine therapy and tumor progression is characterized by androgenindependent growth despite high levels of AR expression in metastatic disease. We inhibited AR expression in LNCaP prostate tumor cells by using antisense AR oligodeoxynucleotides (ODNs) and explored whether antisense AR treatment would be conceivable as a therapy for advanced prostate cancer. Among the various AR antisense ODNs tested, a 15-base ODN targeting the CAG repeats encoding the poly-glutamine region of the AR (as750/15) was found to be most effective. Treatment of LNCaP cells with as750/15 reduced AR expression to ϳ2% within 24 hours compared with mock-treated controls. AR down-regulation resulted in significant cell growth inhibition, strongly reduced secretion of the androgen-regulated prostate-specific antigen, reduction of epidermal growth factor receptor expression, and an increase in apoptotic cells. Mis-sense and mismatched control ODNs had no or only slight effects. Antisense inhibition was also very efficient in LNCaP-abl cells, a subline established after long-term androgen ablation of LNCaP cells, resulting in inhibition of AR expression and cell proliferation that was similar to that seen for parental LNCaP cells. This study shows that inhibition of AR expression by antisense AR ODNs may be a promising new approach for treatment of advanced human prostate cancer. Cancer Gene Therapy (2000) 7, 997-1007

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BACKGROUND Androgen receptor (AR) transcriptional activity is modulated by cofactor proteins. They act as costimulators, corepressors, or bridging proteins, and a disbalanced expression may contribute to the altered activity of the AR in advanced prostate cancer. We investigated the expression of a series of steroid receptor cofactors in prostate cancer cell lines, including several LNCaP sublines, and in prostate stromal cells. METHODS Expression of cofactors was analyzed by means of RT‐PCR in PC‐3, Du‐145, LNCaP, three sublines of LNCaP established after long‐term androgen deprivation, and two strains of primary prostate stroma cells. Expression in LNCaP and LNCaP‐abl cells (which represented an advanced tumor cell) was analyzed employing semiquantitative RT‐PCR. RESULTS Ten of the 12 cofactors tested were expressed in all cells analyzed (AIB1, ARA54, ARA70, CBP, cyclin D1, Her2/neu/erbB2, BAG‐1/M/L, SRC‐1, SMRT, and TIF2). Only ARA55 and FHL2 mRNAs were not detected in all cells. ARA55 mRNA was absent in LNCaP cells, LNCaP sublines, and DU‐145 cells; FHL2 was not expressed in LNCaP cells and its derivatives. The expression pattern was identical in LNCaP cells, and the long‐term androgen ablated LNCaP sublines. Moreover, comparison of expression levels in LNCaP and LNCaP‐abl cells revealed a slight reduction in LNCaP‐abl cells but no gross differences. CONCLUSIONS Prostatic cells express a great number of steroid receptor cofactors. AR activity thus seems to be modulated in a very complex way in prostate cells. Prostate 45:124–131, 2000. © 2000 Wiley‐Liss, Inc.

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