Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides

Currently available methods for treatment of human prostatic carcinoma aim to inactivate the androgen receptor (AR) by androgen deprivation or blockad e with anti-androgens. Failure of endocrine therapy and tumor progression i s characterized by androgen-independent growth despite high levels of AR ex pression in metastatic disease. We inhibited AR expression in LNCaP prostat e tumor cells by using antisense AR oligodeoxynucleotides (ODNs) and explor ed whether antisense AR treatment would be conceivable as a therapy for adv anced prostate cancer. Among the various AR antisense ODNs tested, a 15-bas e ODN targeting the CAG repeats encoding the poly-glutamine region of the A R (as750/15) was found to be most effective. Treatment of LNCaP cells with as750/15 reduced AR expression to similar to 2% within 24 hours compared wi th mock-treated controls. AR down-regulation resulted in significant cell g rowth inhibition, strongly reduced secretion of the androgen-regulated pros tate-specific antigen, reduction of epidermal growth factor receptor expres sion, and an increase in apoptotic cells. Mis-sense and mismatched control ODNs had no or only slight effects. Antisense inhibition was also very effi cient in LNCaP abl cells, a subline established after long-term androgen ab lation of LNCaP cells, resulting in inhibition of AR expression and cell pr oliferation that was similar to that seen for parental LNCaP cells. This st udy shows that inhibition of AR expression by antisense AR ODNs may be a pr omising new approach for treatment of advanced human prostate cancer.