Synergistic Chemosensitization and Inhibition of Progression to Androgen Independence by Antisense Bcl-2 Oligodeoxynucleotide and Paclitaxel in the LNCaP Prostate Tumor Model

Int J Cancer. 2001 Mar 15;91(6):846-50. doi: 10.1002/1097-0215(200002)9999:9999<::aid-ijc1131>3.0.co;2-y.

Abstract

Bcl-2 expression is up-regulated in prostate cancer cells after androgen ablation and associated with development of androgen independence and chemoresistance. We recently reported that antisense Bcl-2 oligodeoxynucleotides (ODNs) delay progression to androgen independence in the androgen-dependent (AD) human LNCaP prostate tumor model. The objectives in this study were to determine whether antisense human Bcl-2 ODN enhances chemosensitivity of paclitaxel and whether combined antisense Bcl-2 ODN and paclitaxel further delays time to androgen-independent (AI) progression in the LNCaP tumor model. Semi-quantitative reverse transcriptast-polymerase chain reaction revealed that treatment of LNCaP cells with antisense Bcl-2 ODN decreased Bcl-2 expression in a dose-dependent and sequence-specific manner, whereas Bcl-2 expression was not affected by paclitaxel treatment. Antisense Bcl-2 ODN treatment significantly enhanced paclitaxel chemosensitivity in vitro, reducing cell viability after treatment with 1 nM paclitaxel from 76% to 42%. Characteristic apoptotic DNA laddering was demonstrated after combined treatment with 500 nM antisense Bcl-2 ODN and 1 nM paclitaxel but not with either agent alone. Adjuvant in vivo administration of combined antisense Bcl-2 and polymeric micellar paclitaxel after castration resulted in a significant delay of emergence of AI recurrent LNCaP tumors compared with either agent alone. By 15 weeks post castration, tumor volume in mice treated with antisense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel was >3-fold higher than in mice treated with combined antisense Bcl-2 ODN and paclitaxel. Mean serum prostate-specific antigen levels returned to or were above precastration levels by 11 weeks post castration in mice treated with antisense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel but remained 90% below the pre-castration level in mice treated with combined antisense Bcl-2 ODN and paclitaxel. These findings identify combined antisense Bcl-2 and paclitaxel as a potentially new therapeutic strategy for advanced prostate cancer by enhancing paclitaxel chemosensitivity and delaying progression of hormone-refractory prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / pharmacology*
  • Animals
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • DNA Primers / chemistry
  • Drug Synergism
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oligonucleotides, Antisense / therapeutic use*
  • Paclitaxel / therapeutic use*
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured / drug effects

Substances

  • Androgens
  • Antineoplastic Agents, Phytogenic
  • DNA Primers
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Prostate-Specific Antigen
  • Paclitaxel