Synergistic inhibitory effects of PTK787/ZK222584 and interferon-alfa on hepatocellular carcinoma with metastatic potential

Abstract

Hepatocellular carcinoma (HCC) patients with metastatic diseasehave a dismal prognosis and effective therapy is urgently needed.Vas-cular endothelial growth factor (VEGF) plays an important role intumor angiogenesis and its receptor is highly expressed in HCC. Our previous study demonstrated that inhibition of VEGF receptors byPTK787/ZK222584 (PTK787) resulted in a significant reduction in tumor volumes in human HCC xenografts established by non-metastatic HCC cell lines. Interferon-alfa (IFN-α) is another agentwith an antiangiogenic property and administration of IFN-α at highdoses inhibited tumor growth in human HCC xenografts withmetastatic potential. The purpose of this study was to investigate theantitumor and antiangiogenic activities of PTK787 alone or in com-bination with IFN-α against HCC xenografts with metastatic poten-tial. The in vitro effect of PTK787 or/and IFN-α on proliferation ofmetastatic human HCC cell lines was studied by MTT assay, whereasapoptosis and cell cycle distribution were evaluated by flow cytome-try. Our results demonstrated that PTK787 inhibited tumor cell pro-liferation, induced tumor cells to undergo apoptosis and delayed cellcycle progression in vitro. IFN-α in combination with PTK787 inhib-ited endothelial cell, but not tumor cell, proliferation. PTK787administration significantly inhibited tumor growth and lung metas-tasis, whereas PTK787 in combination with IFN-α could result in afurther reduction of tumor growth and metastasis. This synergistictherapy significantly inhibited tumor microvessel density, VEGF andmatrix metalloproteinase-2 expression. Our data suggest that VEGFreceptor blockade in combination with IFN-α may provide an effec-tive therapeutic approach for human HCC.