(125)I-labeled anti-bFGF monoclonal antibody inhibits growth of hepatocellular carcinoma.

AIM To investigate the inhibitory efficacy of (125)I-labeled anti-basic fibroblast growth factor (bFGF) monoclonal antibody (mAb) in hepatocellular carcinoma (HCC). METHODS bFGF mAb was prepared by using the 1G9B9 hybridoma cell line with hybridization technology and extracted from ascites fluid through a Protein G Sepharose affinity column. After labeling with (125)I through the chloramine-T method, bFGF mAb was further purified by a Sephadex G-25 column. Gamma radiation counter GC-1200 detected radioactivity of (125)I-bFGF mAb. The murine H22 HCC xenograft model was established and randomized to interventions with control (phosphate-buffered saline), (125)I-bFGF mAb, (125)I plus bFGF mAb, bFGF mAb, or (125)I. The ratios of tumor inhibition were then calculated. Expression of bFGF, fibroblast growth factor receptor (FGFR), platelet-derived growth factor, and vascular endothelial growth factor (VEGF) mRNA was determined by quantitative reverse transcriptase real-time polymerase chain reaction. RESULTS The purified bFGF mAb solution was 8.145 mg/mL with a titer of 1:2560000 and was stored at -20 °C. After coupling, (125)I-bFGF mAb was used at a 1: 1280000 dilution, stored at 4 °C, and its specific radioactivity was 37 MBq/mg. The corresponding tumor weight in the control, (125)I, bFGF mAb, (125)I plus bFGF mAb, and (125)I-bFGF mAb groups was 1.88 ± 0.25, 1.625 ± 0.21, 1.5 ± 0.18, 1.41 ± 0.16, and 0.98 ± 0.11 g, respectively. The tumor inhibition ratio in the (125)I, bFGF mAb, (125)I plus bFGF mAb, and (125)I-bFGF mAb groups was 13.6%, 20.2%, 25.1%, and 47.9%, respectively. Growth of HCC xenografts was inhibited significantly more in the (125)I-bFGF mAb group than in the other groups (P < 0.05). Expression of bFGF and FGFR mRNA in the (125)I-bFGF mAb group was significantly decreased in comparison with other groups (P < 0.05). Groups under interventions revealed increased expression of VEGF mRNA (except for (125)I group) compared with the control group. CONCLUSION (125)I-bFGF mAb inhibits growth of HCC xenografts. The coupling effect of (125)I-bFGF mAb is more effective than the concomitant use of (125)I and bFGF mAb.

[1]  Meng Xu,et al.  Molecular mechanism of reversal effect of monoclonal antibody to basic fibroblast growth factor-mediated expression of P-glycoprotein on multiple drug resistance in adriamycin-resistant human breast cancer cell line MCF-7/ADM , 2013 .

[2]  M. Kojiro,et al.  Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines , 1996, Hepatology.

[3]  Xiuchao Wang,et al.  Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis. , 2013, Biochemical and biophysical research communications.

[4]  Wang Pan-pan.  Synergistic inhibitory effects of bFGF monoclonal antibody combined with radiotherapy on B16-transplanted tumors in mice , 2011 .

[5]  D. Woodfield.  Hepatocellular carcinoma. , 1986, The New Zealand medical journal.

[6]  Lihong V Wang,et al.  A Novel Monoclonal Antibody to Fibroblast Growth Factor 2 Effectively Inhibits Growth of Hepatocellular Carcinoma Xenografts , 2012, Molecular Cancer Therapeutics.

[7]  Yi Lv,et al.  Overexpression of platelet-derived growth factor receptor alpha promotes tumor progression and indicates poor prognosis in hepatocellular carcinoma , 2014, Oncotarget.

[8]  Wang Pan-pan.  Synergistic inhibitory effects of bFGF monoclonal antibody and S-1 against proliferation of lung cancer Lewis cells and angiogenesis of transplanted tumors , 2011 .

[9]  Ke-Cheng Xu,et al.  Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma. , 2013, World journal of gastroenterology.

[10]  S. Fan,et al.  Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. , 2001, American journal of surgery.

[11]  A. Zhu,et al.  Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma , 2012, Oncology.

[12]  T. Betsuyaku,et al.  Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC , 2013, Molecular Cancer Research.

[13]  Lei Chen,et al.  Sulfatase 1 (hSulf-1) reverses basic fibroblast growth factor-stimulated signaling and inhibits growth of hepatocellular carcinoma in animal model , 2014, Oncotarget.

[14]  Wei Zhang,et al.  Predictive value of quantitative contrast-enhanced ultrasound in hepatocellular carcinoma recurrence after ablation. , 2015, World journal of gastroenterology.

[15]  A. Iafrate,et al.  Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[16]  I. Schmidtmann,et al.  Increased basic fibroblast growth factor release and proliferation in xenotransplanted squamous cell carcinoma after combined irradiation/anti-vascular endothelial growth factor treatment. , 2012, Oncology reports.

[17]  Myeong Jun Song,et al.  Outcome of transarterial chemoembolization-based multi-modal treatment in patients with unresectable hepatocellular carcinoma. , 2015, World journal of gastroenterology.

[18]  N. Lin,et al.  Hypoxia-induced secretion of platelet-derived growth factor-BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor-A. , 2015, Molecular medicine reports.

[19]  V. Tolmachev,et al.  Methods for radiolabelling of monoclonal antibodies. , 2014, Methods in molecular biology.

[20]  Y. Yamashita-Kashima,et al.  Biomarkers for antitumor activity of bevacizumab in gastric cancer models , 2012, BMC Cancer.

[21]  M. Dennis,et al.  Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4 , 2011, mAbs.

[22]  N. Hayashi,et al.  Fibroblast growth factor‐2 enhances NK sensitivity of hepatocellular carcinoma cells , 2012, International Journal of Cancer.

[23]  C. Heldin,et al.  PDGF and vessel maturation. , 2010, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[24]  J. Thiery,et al.  Fibroblast growth factor-2. , 2000, The international journal of biochemistry & cell biology.

[25]  Tae Won Kim,et al.  Fibroblast growth factor receptor isotype expression and its association with overall survival in patients with hepatocellular carcinoma , 2015, Clinical and molecular hepatology.

[26]  Lei Xu,et al.  Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. , 2004, Cancer cell.

[27]  常松 日奈子.  Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells , 2013 .

[28]  M. Shah.  The development of bevacizumab in noncolorectal gastrointestinal malignancies: gastroesophageal, pancreatic, and hepatocellular carcinoma. , 2014, Clinical advances in hematology & oncology : H&O.

[29]  J. Park,et al.  Complete remission of advanced hepatocellular carcinoma by radiofrequency ablation after sorafenib therapy. , 2015, World journal of gastroenterology.

[30]  Bo Sun,et al.  Basic fibroblast growth factor upregulates survivin expression in hepatocellular carcinoma cells via a protein kinase B-dependent pathway. , 2013, Oncology reports.

[31]  Zhiwei Wang,et al.  Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway , 2013, Oncotarget.

[32]  Guihua Chen,et al.  Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial. , 2014, Journal of hepatology.