Rational basis for oligodeoxynucleotides to inhibit collagen synthesis in lung fibroblasts and primary fibroblasts from liver granulomas of Schistosoma mansoni-infected mice

• Published in: Cancer letters Vol. 180; no. 2; pp. 145 - 151
• Main Authors: Cutroneo, Kenneth R, Boros, Dov L
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 28.06.2002; Elsevier; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Collagen; Collagen - biosynthesis; Collagen - genetics; Collagen synthesis; Deoxyribonucleic acid; DNA; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Granuloma - complications; Infections; Liver cancer; Liver cirrhosis; Liver Cirrhosis - complications; Liver Cirrhosis - drug therapy; Liver Diseases - complications; Liver Neoplasms - etiology; Medical sciences; Mice; Mice, Inbred CBA; Oligodeoxyribonucleotides - pharmacology; Oligodeoxyribonucleotides - therapeutic use; Phosphorothioate oligos; Protein synthesis; Proteins; Rats; Rodents; Schistosomiasis granuloma fibroblasts; Schistosomiasis mansoni - complications; Sense oligodeoxynucleotides; Transforming Growth Factor beta - pharmacology; Tumors; Viral infections; Wound Healing; Sense oligodeoxynucleotides; Collagen synthesis; Schistosomiasis granuloma fibroblasts; Phosphorothioate oligos; Cell culture; Granuloma; Transforming growth factor β; Transcription promoter; Liver; Trematode disease; Hepatic disease; Hepatocellular carcinoma; Anticarcinogen; Carcinogenesis; Trematoda; Prevention; Schistosomiasis; Double stranded DNA; Collagen type I; Schistosoma mansoni; Rodentia; Plathelmintha; Single stranded DNA; Parasitosis; Malignant tumor; Antisense oligonucleotide; Helminthiasis; In vitro; Biological activity; Infection; Vertebrata; Mammalia; Mouse; Animal; Fibrosis; Helmintha; Digestive diseases; Antisense DNA; Invertebrata; Fibroblast
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(02)00026-5

Hepatocellular carcinoma is associated with liver fibrosis. Murine schistosomiasis infection offers a model to study hepatic fibrogenesis. Single-stranded phosphorothiate oligodeoxynucleotides containing the TGF-β regulatory element have been shown to regulate the transcription of this gene and effectively inhibit collagen synthesis in primary fibroblasts isolated from schistosomiasis-induced hepatic granulomas. While the single-stranded oligos did not decrease collagen and non-collagen protein synthesis below control levels, their double-stranded modified and unmodified counterparts did. Competitive cold oligodeoxynucleotide gel mobility shift analysis using control fibroblast nuclear extract demonstrated that the single-stranded oligos diminished binding of the TGF-β activator protein to the TGF-β regulatory element while the double-stranded oligos totally inhibited this binding. TGF-β element containing single-stranded phosphorothioate oligodeoxynucleotides and their double-stranded counterparts may be successful therapeutic agents to inhibit hepatic fibrogenesis and associated hepatocellular carcinoma.