Inhibition of gene expression and cell proliferation by triple helix-forming oligonucleotides directed to the c-myc gene.
Triple helix-forming oligonucleotides (TFOs) bind with high affinity and specificity to homopurine-homopyrimidine sequences in DNA and have been shown to inhibit transcription of target genes in various experimental systems. In the present study, we evaluated the ability of 3'-amino-modified phosphodiester TFOs directed to four sites in the c-myc gene to inhibit gene expression and proliferation of human leukemia (CEM, KG-1, and HL-60) and lymphoma (Raji and ST486) cells. GT-rich TFOs were designed to target sequences located either upstream (myc1 and -2) or downstream (myc3 and -4) of the P2 promoter, which is the major c-myc promoter. Myc2, which was directed to a site immediately upstream of this promoter, inhibited c-myc expression and proliferation of CEM cells. The effects of this TFO were sequence- and target-specific, since control oligonucleotides and TFOs directed to other sites were less or not active. Myc2 was also effective in KG-1, HL-60, and Raji cells. In contrast, ST486 cells were more sensitive to myc3, which targets a sequence in intron 1 upstream of the P3 promoter, than myc2. As result of a chromosomal translocation, P3 is the active promoter in ST486 cells. This study demonstrates the activity and specificity of TFOs designed to act as repressors of c-myc gene expression in human leukemia and lymphoma cells. Our results suggest that this is a valid approach to selectively inhibit gene expression and cancer cell growth, and encourage further investigation of its potential applications in cancer therapy.
Catapano
C V
CV
Department of Experimental Oncology and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA. Catapanc@musc.edu
McGuffie
E M
EM
Pacheco
D
D
Carbone
G M
GM
D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation; D016259:Genes, myc; D006801:Humans; D009690:Nucleic Acid Conformation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics*
D016376:Oligonucleotides, Antisense