Modified transarterial chemoembolization with locoregional administration of sorafenib for treating hepatocellular carcinoma: feasibility, efficacy, and safety in the VX-2 rabbit liver tumor model

Seidensticker, Max; Streit, Sebastian; Naß, Norbert; Wybranski, Christian; Jürgens, Julian; Brauner, Jan; Schulz, Nadine; Kalinski, Thomas; Seidensticker, Ricarda; Garlipp, Benjamin; Steffen, Ingo G.; Ricke, Jens; Dudeck, Oliver

doi:10.5152/dir.2016.15462

Cited by 8 publications

(10 citation statements)

References 35 publications

(53 reference statements)

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“…First, increasing evidences found low dose of antiangiogenic treatment was effective in improving the tumor microenvironment (Huang et al, 2013;Zhao et al, 2019). Second, substantial parenchymal damage was seen in rabbits with large dose of antiangiogenic treatment in the study by Seidensticker et al (2016), while no significant liver damage was seen in rabbits with low dose in other study (Chatziioannou et al, 2013).…”

Section: Discussionmentioning

confidence: 87%

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Apatinib-loaded CalliSpheres Beads for embolization in a rabbit VX2 liver tumor: characterization in vitro , pharmacokinetics and tumor response in vivo

Shi

Huang

et al. 2020

Drug Delivery

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Apatinib mesylate is an oral antiangiogenic agent that can inhibit activation of vascular endothelial growth factor receptor-2 tyrosine kinase. However, its therapeutic use in liver cancer is restricted due to severe systemic toxicity. Our work aimed to construct apatinib-loaded CalliSpheres Beads (CBAPA) and investigate its application in transarterial chemoembolization (TACE) of liver cancer. The established stock solution containing 20, 40 or 60 mg apatinib were fully mixed with 100–300 μm CalliSpheres Beads (CB) for 2 hours, respectively. The highest loading efficiency at 30 min after combination in 20 mg group (maximum 70.7%). Further, apatinib can be steadily released from CBAPA in vitro release test. For pharmacokinetics and tumor response in vivo , sixty New Zealand white rabbits with VX2 liver tumor were assigned into four groups: sham (NS) group, apatinib solution alone (APA) group, CB group and CBAPA group. Apatinib was measured in plasma and liver tissue by high performance liquid chromatography–tandem mass spectrometry. Compared to APA group, the administration of apatinib by TACE with CBAPA resulted in low systemic concentration. In addition, intratumoural apatinib concentration was higher than adjacent hepatic parenchyma in the CBAPA group. Compared to other three groups, CBAPA group achieved lower tumor growth rate and improved survival time. In conclusion, these findings provide a basis for the potential application of apatinib-loaded CalliSpheres Beads in liver cancer.

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Section: Discussionmentioning

confidence: 87%

“…Second, substantial parenchymal damage was seen in rabbits with large dose of antiangiogenic treatment in the study by Seidensticker et al. ( 2016 ), while no significant liver damage was seen in rabbits with low dose in other study (Chatziioannou et al., 2013 ).…”

Section: Discussionmentioning

confidence: 89%

Apatinib-loaded CalliSpheres Beads for embolization in a rabbit VX2 liver tumor: characterization in vitro , pharmacokinetics and tumor response in vivo

Shi

Huang

et al. 2020

Drug Delivery

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“…As for the hepatorenal function, donafenib and epirubicin had a similar toxic reaction, which was different with the results in regard to the local administration of sorafenib. 37 The study had several limitations. Firstly, the evaluation of immune response was limited due to the lack of antibody reagents for rabbits, which is the most suitable model for TAE treatment.…”

Section: Discussionmentioning

confidence: 99%

“…As for the hepatorenal function, donafenib and epirubicin had a similar toxic reaction, which was different with the results in regard to the local administration of sorafenib. 37 …”

Section: Discussionmentioning

confidence: 99%

Transcatheter Arterial Embolization Containing Donafenib Induces Anti-Angiogenesis and Tumoricidal CD8+ T-Cell Infiltration in Rabbit VX2 Liver Tumor

Shi¹,

Li²,

Huang³

et al. 2021

CMAR

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To evaluate the effect and immune response of transcatheter arterial embolization (TAE) combined with donafenib in rabbit VX2 liver tumor model. Materials and Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured. Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8 + lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment. Conclusion:The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer.

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“…However, clinical data on this issue so far are inconclusive (12,13). In order to enhance the adjunctive effect of sorafenib combined with TACE and to reduce the sideeffects of systemic sorafenib therapy, local application of sorafenib into the HCC, together with embolic material, is proposed and under initial preclinical research, with promising results (14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Validation of VX2 as a Hepatocellular Carcinoma Model: Comparison of the Molecular Reaction of VX2 and HepG2 Tumor Cells to Sorafenib In Vitro

Naß

Streit

Wybranski

et al. 2017

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As there is currently no superior hepatocellular carcinoma (HCC) model with percutaneous vascular access for transarterial treatments available, the VX2 rabbit model is frequently used for in vivo investigations on liver carcinoma. However, the VX2 cell line was derived from a virus-induced skin papilloma that can form carcinosarcoma in liver of rabbits and the transferability of obtained results to HCC treatment remains open. Here we compared the most frequently investigated human HCC model cell line, HepG2, with VX2 cells in vitro in terms of sensitivity towards the broad specificity kinase inhibitor sorafenib and responsiveness to the addition of platelet-derived growth factor AB (PDGF-AB), vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF), as well as insulin and interleukin-1β (IL1β). Phosphorylation of protein kinase B (AKT) the mitogen-activated protein kinases (MAPKs) p38 and p42/44 (extracellular signal-regulated kinase, ERK1/2) and inhibitor of kappa light chain gene enhancer alpha (IĸBα) was determined by western blotting as these events are associated with early signaling cascades. Additionally, the inhibition of phosphorylation under sorafenib treatment was investigated. Sorafenib was equally toxic to both cell lines, but only in HepG2 was activation of caspase 3/7 activity, as a sign of apoptosis, observed. VX2 cells exhibited generally more intense phosphorylation signals in response to the growth factors and also serum. In contrast to VX2, HepG2 cells showed no response to PDGF-AB or VEGF as determined by kinase phosphorylation. In both cell lines, sorafenib inhibited growth factor-induced phosphorylation of ERK and p38-MAPK. AKT phosphorylation was only inhibited in VX2 cells and IĸBα phosphorylation was not influenced by this kinase inhibitor in either cell type. Taken together, the two cellular models for HCC share several features related to sorafenib application, but differed in their responsiveness towards growth factors. Therefore, results obtained with the VX2 model cannot be extended to human HCC without appropriate caution.

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Modified transarterial chemoembolization with locoregional administration of sorafenib for treating hepatocellular carcinoma: feasibility, efficacy, and safety in the VX-2 rabbit liver tumor model

Cited by 8 publications

References 35 publications

Apatinib-loaded CalliSpheres Beads for embolization in a rabbit VX2 liver tumor: characterization in vitro , pharmacokinetics and tumor response in vivo

Apatinib-loaded CalliSpheres Beads for embolization in a rabbit VX2 liver tumor: characterization in vitro , pharmacokinetics and tumor response in vivo

Transcatheter Arterial Embolization Containing Donafenib Induces Anti-Angiogenesis and Tumoricidal CD8+ T-Cell Infiltration in Rabbit VX2 Liver Tumor

Validation of VX2 as a Hepatocellular Carcinoma Model: Comparison of the Molecular Reaction of VX2 and HepG2 Tumor Cells to Sorafenib In Vitro

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