Human T-cell leukemia virus type I tax transformation is associated with increased uptake of oligodeoxynucleotides in vitro and in vivo.
We have utilized antisense oligodeoxynucleotides (ODNs) to modulate transcriptional activation by the human T-cell leukemia virus type I (HTLV-I) tax gene, the major transcriptional regulator of this virus. 3'-Terminal phosphorothioate-modified antisense ODNs were shown to efficiently inhibit Tax protein expression both in vitro and in vivo. Terminal substitution did not affect the affinity of ODNs for their target sequence but conferred a 9-fold increase in tax inhibition in vitro. When delivered into mice by intraperitoneal injection, ODNs inhibited tax expression in established tumors by 90%. Unmanipulated tax-transformed mouse fibroblasts, or HTLV-I-transformed human lymphocytes, showed at least 5-fold higher ODN binding and uptake over control cells. Balb/3T3 cell binding was induced to similar levels by cellular activators. This suggests that constitutive activation by tax transformation may increase susceptibility of HTLV-I-transformed cells to antisense therapy, providing a rationale for the use of antisense ODN therapeutics in HTLV-I-associated diseases.
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D015152:Blotting, Northern; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005260:Female; D016355:Genes, pX / Q000187:drug effects*; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000378:metabolism* / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000378:metabolism* / Q000494:pharmacology*; D009928:Organ Specificity; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012091:Repetitive Sequences, Nucleic Acid; D015533:Transcriptional Activation / Q000187:drug effects*
D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012313:RNA