Down-regulation of c-MYC antigen expression in lymphocytes of Emu-c-myc transgenic mice treated with anti-c-myc DNA methylphosphonates.
In transgenic mice bearing a murine immunoglobulin enhancer/c-myc fusion transgene (Emu-myc), it was found that antisense DNA methylphosphonates targeted against c-myc mRNA inhibited production of c-MYC protein in peripheral lymphocytes. The decrease in protein was measured 3-4 h after i.v. administration of a 300-nmol dose. c-MYC was detected by immunofluorescence of fixed cells stained with an anti-c-MYC antiserum. In addition, DNA methylphosphonates did not induce acute toxicity following i.v. administration of a 300-nmol dose. An identically administered scrambled sequence oligomer did not decrease c-MYC protein or induce toxicity. Finally, recovery of DNA methylphosphonates from the blood plasma of treated mice indicated that the oligomers remained intact up to 3 h, while their concentrations decreased rapidly for the first h, then slowly decreased over the next 2 h. This is the first demonstration of sequence-specific antisense DNA methylphosphonate inhibition of gene expression in the bloodstream of an animal model.
Wickstrom
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Department of Chemistry, University of South Florida, Tampa 33620.
Bacon
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Wickstrom
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D000818:Animals; D001483:Base Sequence; D016373:DNA, Antisense / Q000494:pharmacology*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D016259:Genes, myc; D008214:Lymphocytes / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000097:blood*; D012333:RNA, Messenger / Q000032:analysis
D016373:DNA, Antisense; D009943:Organophosphorus Compounds; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C032627:methylphosphonic acid