REVERSAL OF CHEMORESISTANCE OF LYMPHOMA-CELLS BY ANTISENSE-MEDIATED REDUCTION OF BCL-2 GENE-EXPRESSION

The bcl-2 gene is expressed in many types of human tumors and becomes transcriptionally deregulated in the majority of non-Hodgkin's lymphom as as the result of t(14;18) chromosomal translocations. The 26-kDa Bc l-2 protein has been shown to block programmed cell death (apoptosis) induced by many types of stimuli, including a wide variety of chemothe rapeutic 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 res istance, we used antisense (As) approaches to achieve reductions in th e levels of steady state Bcl-2 protein levels in t(14; 18)-containing human lymphoma cell lines. Both synthetic bcl-2-As oligonucleotides an d inducible expression plasmids that produce bcl-2-As transcripts indu ced reductions in bcl-2 expression, resulting in a marked enhancement in the sensitivity of neoplastic cells to conventional chemotherapeuti c drugs such as cytosine arabinoside (ara-C) and methotrexate (MTX). T hese results suggest that novel therapeutics targeted against bcl-2 co uld provide the means for improved treatment of cancer by affecting ph ysiological pathways distal to the targets of cytotoxic drugs.