Antisense BcI-2 oligodeoxynucleotides inhibit progression to androgen-independence after castration in the Shionogi tumor model

Progression to androgen-independence remains the main obstacle to improving survival for patients with advanced prostate cancer. Although Bcl-2 expres sion in normal prostatic epithelial cells is low or absent, Bcl-2 is highly up-regulated in prostate cancer cells after androgen withdrawal and during progression to androgen-independence. Here, me test the efficacy of antise nse Bcl-2 oligodeoxynucleotide (ODN) therapy administered adjuvantly after castration to delay time to androgen-independent recurrence in the androgen -dependent mouse Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with antisense Bcl-2 ODN inhibited Bcl-2 expression in a dose-depend ent and sequence-specific manner, Systemic administration of antisense Bcl- 2 ODN in mice bearing Shionogi tumors beginning 1 day postcastration result ed in a more rapid regression of tumors and a significant delay of emergenc e of androgen-independent recurrent tumors, Furthermore, despite significan t reduction of Bcl-2 expression in tumor tissues, antisense Bcl-2 ODN had n o effect on Bcl-2 expression in normal mouse organs, These findings illustr ate the potential utility of antisense Bcl-2 therapy for prostate cancer in an adjuvant setting with androgen ablation.