Antisense Bcl-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 expression 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, we test the efficacy of antisense 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-dependent and sequence-specific manner. Systemic administration of antisense Bcl-2 ODN in mice bearing Shionogi tumors beginning 1 day postcastration resulted in a more rapid regression of tumors and a significant delay of emergence of androgen-independent recurrent tumors. Furthermore, despite significant reduction of Bcl-2 expression in tumor tissues, antisense Bcl-2 ODN had no effect on Bcl-2 expression in normal mouse organs. These findings illustrate the potential utility of antisense Bcl-2 therapy for prostate cancer in an adjuvant setting with androgen ablation.
Miyake
H
H
The Prostate Centre, Vancouver General Hospital, British Columbia, Canada.
Tolcher
A
A
Gleave
M E
ME
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D005260:Female; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism
D000728:Androgens; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2