Intravenous injection of oligodeoxynucleotides to the NF-kappaB binding site inhibits hepatic metastasis of M5076 reticulosarcoma in mice.
We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation in vivo. In the present study, we employed decoy ODN targeting the transcription factor nuclear factor-kappaB (NF-kappaB) binding cis-elements to hepatic metastasis of murine reticulosarcoma M5076 in mice. Intravenous inoculation of M5076 into mice caused a marked increase in gene expression of interleukin-1beta, tumor necrosis factor-alpha and intercellular adhesion molecule-1 in the liver, whereas intravenous treatment with NF-kappaB decoy ODN reduced M5076-induced transactivation of these genes. Treatment with NF-kappaB decoy ODN, but not scrambled decoy ODN, significantly inhibited hepatic metastasis of M5076 in mice, and furthermore the combined treatment of NF-kappaB decoy ODN with an anti-cancer drug resulted in complete inhibition of hepatic metastasis in half of the mice, without affecting myelosuppression induced by the anti-cancer drug. Here, NF-kappaB decoy ODN inhibited hepatic metastasis of M5076 in mice possibly through a decrease in transactivation of important NF-kappaB-driven genes and also potentiated the anti-metastatic effect of an anti-cancer drug, demonstrating the first successful in vivo therapy for cancer metastasis using NF-kappaB decoy ODN as a novel molecular decoy approach.
Kawamura
I
I
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Morishita
R
R
Tsujimoto
S
S
Manda
T
T
Tomoi
M
M
Tomita
N
N
Goto
T
T
Ogihara
T
T
Kaneda
Y
Y
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001665:Binding Sites; D003131:Combined Modality Therapy; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D008081:Liposomes; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000556:secondary* / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000627:therapeutic use; D016328:NF-kappa B / Q000235:genetics*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D018108:Respirovirus / Q000235:genetics; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D007375:Interleukin-1; D008081:Liposomes; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016685:Mitomycin