ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide. At present, effective therapeutic options available for HCC are limited; consequently, the prognosis for these patients is poor. Our aim in the present study was to identify a novel target for antibody therapy against HCC. METHODOLOGY/PRINCIPAL FINDINGS: We used Western blot and flow cytometric and immunocytochemical analyses to investigate the regulation of FGFR1 expression by interferon-α/ß in several human hepatic cancer cell lines. In addition, we tested the efficacy of combined treatment with anti-FGFR1 monoclonal antibody and interferon-α/ß in a murine xenograft model of human HCC. We found that interferon-α/ß induces expression of FGFR1 in human HCC cell lines, and that an anti-FGFR1 monoclonal antibody (mAb) targeting of the induced FGFR1 can effectively inhibit growth and survival of HCC cells in vitro and in vivo. Moreover, the combination of interferon-α, anti-FGFR1 mAb and peripheral blood mononuclear cells (PBMCs) exerted a significant antitumor effect in vitro. CONCLUSIONS: Our results suggest that the combined use of an anti-FGFR1 antibody and interferon-α/ß is a promising approach to the treatment of HCC.
Subject(s)
Antibodies, Monoclonal/pharmacology , Carcinoma, Hepatocellular/pathology , Interferon-alpha/pharmacology , Interferon-beta/pharmacology , Liver Neoplasms/pathology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Animals , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Liver Neoplasms/metabolism , Mice , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND/AIMS: Preclinical assessment of radio-labeled monoclonal antibodies is essential to the understanding of target-specific tumor localization. The purpose of this study is to prepare for fundamental evaluation of antibodies and to validate the clinical usefulness of the candidate considered useful for practice through preclinical assessment. METHODOLOGY: The immunoreactivity and affinity constant of three kinds of monoclonal antibody (1A4, 1B2, 4H11: CEA-specific) were evaluated with the method of cell binding assay. Tumor localization and biodisrtibution were performed in tumor-bearing athymic mice. Five patients of colorectal cancer underwent radioimmunodetection with 99mTc. Histological analysis was performed to evaluate the tumor localization of injected antibody. RESULTS: The immunoreactive fraction value of 1B2 is the highest than the other antibodies. The difference between the antibody affinities among three antibodies although were rather small. In an animal model, 1B2 obtained more highly tumor targeting and cleared more rapidly from the blood than the other two antibodies did. Pilot study using 1B2 was successful in all cases without background imaging. Visualization of tumor sites surgically removed revealed positive CEA and IgG immunostaining. CONCLUSION: The preparation for preclinical assessment of the characteristic parameters is practically valuable for clinical application of radiolabeled antibodies.
