Progression to Androgen Independence Is Delayed by Adjuvant Treatment with Antisense Bcl-2 Oligodeoxynucleotides after Castration in the LNCaP Prostate Tumor Model

• Published in: Clinical cancer research 1999-10, Vol.5 (10), p.2891-2898
• Main Authors: GLEAVE, M, TOLCHER, A, MIYAKE, H, NELSON, C, BROWN, B, BERALDI, E, GOLDIE, J
• Format: Article
• Language: English
• Subjects: Androgens - pharmacology; Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Chemotherapy; Humans; Male; Medical sciences; Mice; Mice, Inbred BALB C; Oligonucleotides, Antisense - therapeutic use; Orchiectomy; Pharmacology. Drug treatments; Prostate-Specific Antigen - blood; Prostatic Neoplasms - drug therapy; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; RNA, Messenger - analysis
• ISSN: 1078-0432; 1557-3265

Bcl-2 has emerged as a critical regulator of apoptosis in a variety of cell systems and is up-regulated during progression to androgen independence in prostate cancer cells. The objectives of this study were to characterize changes in Bcl-2 after androgen withdrawal and during progression to androgen independence in the human prostate LNCaP tumor model and determine whether adjuvant use of antisense Bcl-2 oligodeoxynucleotides (ODNs) with androgen ablation delays progression to androgen independence. Bcl-2 expression in LNCaP cells is down-regulated to undetectable levels by androgen in vitro and up-regulated after castration in vivo . Antisense Bcl-2 ODN treatment reduced LNCaP cell Bcl-2 messenger RNA and protein levels by >90% in a sequence-specific and dose-dependent manner at concentrations >50 n m . Bcl-2 mRNA levels returned to pretreatment levels by 48 h after discontinuing treatment. Athymic male mice bearing SQ LNCaP tumors were castrated and injected i.p. with 12.5 mg/kg/day with two-base mismatch ODN control, reverse polarity ODN control, or antisense Bcl-2 ODN. Tumor volume in control mice gradually increased 5-fold (range, 3–6) by 12 weeks after castration compared to a 10–50% decrease in precastrate tumor volume in mice treated with antisense Bcl-2 ODN. Changes in serum PSA paralleled changes in tumor volume, increasing 4-fold faster above nadir in controls than in mice treated with antisense Bcl-2 ODN. After decreasing 70% by 1 week after castration, PSA increased 1.6-fold above precastrate levels by 11 weeks in controls while staying 30% below precastrate levels in antisense-treated mice. In a second group of experiments, LNCaP tumor growth and serum PSA levels were 90% lower ( P < 0.01) in mice treated with antisense Bcl-2 ODN compared with mismatch or reverse polarity ODN controls. These results support the hypothesis that Bcl-2 helps mediate progression to androgen independence and is an appropriate target for antisense therapy.