Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression

Antisense Res Dev. Summer 1994;4(2):71-9. doi: 10.1089/ard.1994.4.71.

Abstract

The bcl-2 gene is expressed in many types of human tumours and becomes transcriptionally deregulated in the majority of non-Hodgkin's lymphomas as the result of t(14;18) chromosomal translocations. The 26-kDa Bcl-2 protein has been shown to block programmed cell death (apoptosis) induced by many types of stimuli, including a wide variety of chemotherapeutic drugs and radiation. The presence of bcl-2 in tumor cells has been correlated with poor responses to therapy in patients with some types of cancer. To explore further the relevance of bcl-2 to drug resistance, we used antisense (As) approaches to achieve reductions in the levels of steady state Bcl-2 protein levels in t(14;18)-containing human lymphoma cell lines. Both synthetic bcl-2-As oligonucleotides and inducible expression plasmids that produce bcl-2-As transcripts induced reductions in bcl-2 expression, resulting in a marked enhancement in the sensitivity of neoplastic cells to conventional chemotherapeutic drugs such as cytosine arabinoside (ara-C) and methotrexate (MTX). These results suggest that novel therapeutics targeted against bcl-2 could provide the means for improved treatment of cancer by affecting physiological pathways distal to the targets of cytotoxic drugs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Chromosomes, Human, Pair 14*
  • Clone Cells
  • Drug Resistance / genetics
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lymphoma / drug therapy*
  • Lymphoma / genetics
  • Mice
  • Oligonucleotides, Antisense / pharmacology*
  • Translocation, Genetic*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Oligonucleotides, Antisense