Antitumor effect of vascular endothelial growth factor inhibitor sunitinib in preclinical models of hepatocellular carcinoma.
OBJECTIVE
Tumor recurrence and metastasis is the most common cause of mortality in hepatocellular carcinoma (HCC) patients. Despite positive results with vascular endothelial growth factor (VEGF) inhibitors in preclinical studies using HCC xenograft models, the clinical outcome in HCC patients has been disappointing. So far, only the multitargeted tyrosine kinase inhibitor sorafenib has been shown to significantly improve survival in HCC patients, suggesting that this class of agents could be effective against HCC. Recently, another VEGF inhibitor, sunitinib, showed survival benefits in HCC hepatitis B-positive patients, but failed to improve survival in HCC hepatitis C-positive patients. Obviously, concomitant liver disease, liver function in general, and the local liver environment have a huge impact on treatment outcomes. In this study, we aimed to examine the antiproliferative effect of sunitinib in different HCC cell lines in vitro, and then in xenograft and orthotopic models of HCC in order to assess the effect of the local liver vasculature on drug efficacy.


METHODS
Human cancer cell lines Huh7.5, Hep3B, and SK-Hep-1 were used for in-vitro studies. In in-vivo studies, each mouse carried Huh7.5 cells in both the subcutaneous and the intrahepatic compartment; therefore, drug exposure and treatment regimen were identical in both tumors.


RESULTS
Sunitinib has the potential to moderately inhibit proliferation in the Huh7.5 cell line, induce p53 in the p53-wild-type cell line SK-hep-1, and to increase the S-phase and the sub-G1 component of the cell cycle in the Hep3B cell line. Diverse responses to sunitinib in HCC cell lines emphasize the heterogeneity of HCC tumors and may further explain the discrepancy between preclinical and clinical results. The in-vivo results show that sunitinib treatment was far less effective against intrahepatic tumors compared with xenografts. Histological data indicate that large solid intrahepatic tumors are severely affected by sunitinib as shown by large areas of necrosis and diminished number of viable tumor cells.


CONCLUSIONS
The real problem when treating intrahepatic tumors with sunitanib and/or other VEGF inhibitors seems to arise from unopposed local growth of the small tumors and perhaps the development of distant micrometastases. Even though both xenograft and orthotopic models have limitations, these models add value to our understanding of tumor biology and help to better design treatment paradigms for patients with HCC. In comparison with xenograft models, the orthotopic HCC model allows for a more realistic assessment of drug efficacy in patients, in particular by enhancing our knowledge of the role that organ vasculature plays in the development of local metastasis and tumor resistance to antiangiogenic treatments.
Worldwide Comparative Medicine, GS&T, Groton, Connecticut, USA. cedo.bagi@pfizer.com
Cedo Martin
CM
Bagi
David F
DF
Gebhard
Catharine J
CJ
Andresen
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D000077210:Sunitinib; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib