title: Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice.
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.
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Wei-Hsiang
authors.initials: WH
authors.lastname: Lin
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Shiou-Hwei
authors.initials: SH
authors.lastname: Yeh
authors.affiliation: Department of Oncology, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Kun-Huei
authors.initials: KH
authors.lastname: Yeh
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Kai-Wei
authors.initials: KW
authors.lastname: Chen
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Tung-Hung
authors.initials: TH
authors.lastname: Su
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Ping
authors.initials: P
authors.lastname: Jao
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Lin-Chun
authors.initials: LC
authors.lastname: Ni
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan; chends@ntu.edu.tw peijerchen@ntu.edu.tw.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan chends@ntu.edu.tw peijerchen@ntu.edu.tw.
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006499:Hepatic Artery / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D008026:Ligation; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology* / Q000628:therapy; D008279:Magnetic Resonance Imaging; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009336:Necrosis; D012008:Recurrence; D000077704:Tirapazamine; D015534:Trans-Activators / Q000235:genetics*; D014227:Triazines / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D015534:Trans-Activators; D014227:Triazines; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D000077704:Tirapazamine
keywords: hepatocellular carcinoma; hypoxia; orthotopic; transarterial embolization