Cancer research (Chicago, Ill.), 2011-12, Vol.71 (24), p.7608-7616
2011
Details
- Autor(en) / Beteiligte
- Titel
- miR-221 Silencing Blocks Hepatocellular Carcinoma and Promotes Survival
- Ist Teil von
- Cancer research (Chicago, Ill.), 2011-12, Vol.71 (24), p.7608-7616
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis because of a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221, which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2'-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared with unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell-cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment for patients with advanced HCC.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-11-1144Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3773601
- Format
- –
- Schlagworte
- Animals, Antineoplastic agents, Apoptosis - drug effects, Biological and medical sciences, Blotting, Northern, Carcinoma, Hepatocellular - genetics, Carcinoma, Hepatocellular - pathology, Carcinoma, Hepatocellular - therapy, Cell Cycle - drug effects, Cell Line, Tumor, Cell Proliferation - drug effects, Cholesterol - chemistry, Female, Gastroenterology. Liver. Pancreas. Abdomen, Gene Silencing, Humans, In Situ Hybridization, Kaplan-Meier Estimate, Liver - drug effects, Liver - metabolism, Liver - pathology, Liver Neoplasms, Experimental - genetics, Liver Neoplasms, Experimental - pathology, Liver Neoplasms, Experimental - therapy, Liver. Biliary tract. Portal circulation. Exocrine pancreas, Medical sciences, Mice, Mice, Inbred C57BL, MicroRNAs - genetics, Oligonucleotides, Antisense - genetics, Oligonucleotides, Antisense - pharmacokinetics, Oligonucleotides, Antisense - pharmacology, Pharmacology. Drug treatments, Reverse Transcriptase Polymerase Chain Reaction, Transfection - methods, Tumors, Xenograft Model Antitumor Assays - methods