title: Molecularly Targeted Therapy of Human Hepatocellular Carcinoma Xenografts with Radio-iodinated Anti-VEGFR2 Murine-Human Chimeric Fab.
abstract: Vascular endothelial growth factor receptor 2 (VEGFR2) is traditionally regarded as an important therapeutic target in a wide variety of malignancies, such as hepatocellular carcinoma (HCC). We previously generated a murine-human anti-VEGFR2 chimeric Fab (cFab), named FA8H1, which has the potential to treat VEGFR2-overexpressing solid tumors. Here, we investigated whether FA8H1 can be used as a carrier in molecularly targeted therapy in HCC xenograft models. FA8H1 was labeled with (131)I, and two HCC xenograft models were generated using BEL-7402 (high VEGFR2-expressing) and SMMC-7721 (low VEGFR2-expressing) cells, which were selected from five HCC cell lines. The biodistribution of (131)I-FA8H1 was determined in both models by Single-Photon Emission Computed Tomography and therapeutic effects were monitored in nude mice bearing BEL-7402 xenografts. Finally, we determined the involvement of necrosis and apoptotic pathways in treated mice using immunohistochemistry. (131)I-FA8H1 levels were dramatically reduced in blood and other viscera. The therapeutic effect of (131)I-labeled FA8H1 in the BEL-7402 model was significantly better than that by (131)I and FA8H1 alone. We observed extensive necrosis in the treated tumors, and both FasL and caspase 3 were up-regulated. Thus, (131)I-anti-VEGFR2 cFab has the potential to be used for molecularly targeted treatment of HCC overexpressing VEGFR2.
authors.affiliation: 1] Key Laboratory of Antibody Technique, Ministry of Health, Nanjing Medical University, Nanjing, Jiangsu 210029, China [2] Department of Pathology, Affiliated Hospital of Nantong University. Nantong, Jiangsu 226001, China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory of Antibody Technique, Ministry of Health, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Huadong Medical Institute of Biotechniques, Nanjing, Jiangsu 210002, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Yu
authors.affiliation: 1] Key Laboratory of Antibody Technique, Ministry of Health, Nanjing Medical University, Nanjing, Jiangsu 210029, China [2] Jiangsu Key Lab of Cancer Biomarkers, Prevention &Treatment, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Feng
authors.affiliation: 1] Key Laboratory of Antibody Technique, Ministry of Health, Nanjing Medical University, Nanjing, Jiangsu 210029, China [2] Huadong Medical Institute of Biotechniques, Nanjing, Jiangsu 210002, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage; D007457:Iodine Radioisotopes / Q000276:immunology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2