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Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Oct 18; Vol. 113 (42), pp. 11937-11942. Date of Electronic Publication: 2016 Oct 04. - Publication Year :
- 2016
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Abstract
- Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification because of its exclusive arterial blood supply. Although TACE achieves substantial necrosis of the tumor, complete tumor necrosis is uncommon, and the residual tumor generally rapidly recurs. We combined tirapazamine (TPZ), a hypoxia-activated cytotoxic agent, with hepatic artery ligation (HAL), which recapitulates transarterial embolization in mouse models, to enhance the efficacy of TACE. The effectiveness of this combination treatment was examined in HCC that spontaneously developed in hepatitis B virus X protein (HBx) transgenic mice. We proved that the tumor blood flow in this model was exclusively supplied by the hepatic artery, in contrast to conventional orthotopic HCC xenografts that receive both arterial and venous blood supplies. At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells. This combination treatment clearly limited the toxicity of TPZ to HCC, which caused the rapid and near-complete necrosis of HCC. In conclusion, the combination of TPZ and HAL showed a synergistic tumor killing activity that was specific for HCC in HBx transgenic mice. This preclinical study forms the basis for the ongoing clinical program for the TPZ-TACE regimen in HCC treatment.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Biomarkers
Carcinoma, Hepatocellular mortality
Carcinoma, Hepatocellular therapy
Cell Line, Tumor
Combined Modality Therapy
Disease Models, Animal
Dose-Response Relationship, Drug
Hepatic Artery surgery
Humans
Immunohistochemistry
Ligation
Liver Neoplasms therapy
Magnetic Resonance Imaging
Mice
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Necrosis
Recurrence
Tirapazamine
Tumor Burden drug effects
Viral Regulatory and Accessory Proteins
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Carcinoma, Hepatocellular etiology
Carcinoma, Hepatocellular pathology
Liver Neoplasms etiology
Liver Neoplasms pathology
Trans-Activators genetics
Triazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 42
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27702890
- Full Text :
- https://doi.org/10.1073/pnas.1613466113