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 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.
Kitada
S
S
La Jolla Cancer Research Foundation, Cancer Research Center, California 92037.
Takayama
S
S
De Riel
K
K
Tanaka
S
S
Reed
J C
JC
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002883:Chromosomes, Human, Pair 14; D002999:Clone Cells; D004351:Drug Resistance / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense