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Optimizing chemotherapy for transitional cell carcinoma by application of bcl-2 and bcl-xL antisense

Christian Bolenz1, Andreas Becker, Lutz Trojan

  • 1Department of Urology, University Hospital Mannheim, Mannheim, Germany. christian.bolenz@uro.ma.uni-heidelberg.de

Urologic Oncology
|December 1, 2007
PubMed
Abstract

Insights

Antiapoptotic proteins Bcl-2 and Bcl-xL contribute to chemoresistance in transitional cell carcinoma (TCC). Combining antisense oligodeoxynucleotides (AS-ODNs) targeting these proteins with chemotherapy significantly enhanced cancer cell death in TCC cell lines.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Transitional cell carcinoma (TCC) exhibits high therapy failure rates with conventional chemotherapy.
  • Antiapoptotic proteins, specifically Bcl-2 and Bcl-xL, are implicated in promoting chemoresistance in TCC.
  • Antisense oligodeoxynucleotides (AS-ODNs) offer a targeted approach to downregulate specific messenger ribonucleic acid (mRNA) expression.

Purpose of the Study:

  • To investigate the potential of combining AS-ODNs targeting Bcl-2 and Bcl-xL with chemotherapeutic agents.
  • To evaluate the enhanced cytotoxic effects of this combined treatment compared to monotherapy in TCC cell lines.
  • To assess the impact on chemoresistance mechanisms in TCC.

Main Methods:

  • Western blot and immunohistochemistry were used to confirm Bcl-2 and Bcl-xL expression in TCC cell lines.
  • TCC cell lines were treated with chemotherapeutic agents (cisplatin, gemcitabine, mitomycin C, paclitaxel) alone and in combination with Bcl-2 or Bcl-xL AS-ODNs.
  • Cell viability was quantified using MTT assays and Neubauer hemocytometry.

Main Results:

  • All TCC cell lines demonstrated a dose-dependent response to chemotherapeutic monotherapy.
  • Combined treatment with AS-ODNs and chemotherapy resulted in significantly higher cell death rates compared to monotherapy.
  • For example, paclitaxel combined with Bcl-xL AS-ODNs increased cell death from 30.3% to 87.2% in HT 1197 cells.
  • Statistical analysis confirmed a significant effect of combined treatment across all tested cell lines.

Conclusions:

  • The addition of Bcl-2 and Bcl-xL AS-ODNs significantly enhances the cytotoxic efficacy of chemotherapeutic agents against TCC cell lines.
  • This synergistic effect suggests a promising strategy for overcoming chemoresistance in TCC.
  • Further preclinical investigations in ex vivo and in vivo models are warranted to support future clinical applications.

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