Trans-arterial gene therapy for hepatocellular carcinoma in a rabbit model

Abstract

Aim: To study the effect of adenovirus (Ad)-p53 gene therapy on hepatocellular carcinoma (HCC) in a rabbit model.

Methods: VX2 tumor was grown in the liver of 24 rabbits. Animals were divided into four groups: group A receiving trans-arterial gene therapy (Ad-p53) only, group B receiving combined Ad-p53 therapy and trans-arterial embolization (lipiodol), group C receiving trans-arterial chemoembolization (lipiodol + mitomycin C), control group (D) receiving sodium chloride. Tumor volume (V1) was measured by using MRI (d 13). Interventional procedure was applied (d 14). Tumor volume (V2) was assessed by MRI (d 21) and the mean ratio (V2/V1) was calculated. After the second MRI, specimens of the liver were abstained and examined immunohistochemically using mutant-type p53 antibody. The positive expression was scored.

Results: Compared with control group (chi= 3.14 +/- 0.64), therapeutic groups all showed a significant decrease in the tumor growth ratio (P<0.05). A slight difference was found between group A (chi = 2.35 +/- 0.59) and group B (chi = 1.75 +/- 0.28) (P=0.048). No statistically significant difference was observed between group B and group C (chi = 2.00 +/- 0.44). The positive expression rate of mutant-type p53 was the lowest in group B and significantly different between group A and group C (P<0.05). Compared to the control subjects, groups A and C both showed a decrease in the expression of mutant-type p53, but there was no significant difference between them.

Conclusion: Trans-arterial Ad-p53 gene therapy can reduce tumor growth of HCC in rabbit model.

Figure 1

Images in a VX2 rabbit with a solid HCC in group B. A: Pretherapeutic unenhanced T2-weighted axial MR imaging with FSE sequence (3000/89.2). The hyperintense lesion with a size of 9 mm×10 mm is well discernible from the surrounding liver tissue. B: Post-therapeutic unenhanced T2-weighted axial MR imaging with FSE sequence (3000/89.2) showing the hyperintense lesion (15 mm × 11 mm) with central hypointense area corresponding to the intratumoral necrosis.

Figure 2

Images in a VX2 rabbit with a solid HCC in group D. A: Pretherapeutic unenhanced T2-weighted axial MR imaging with FSE sequence (3000/89.2). The hyperintense lesion with a size of 12 mm × 13 mm is well discernible from the surrounding liver tissue; B: Post-therapeutic unenhanced T2-weighted axial MR imaging with FSE sequence (3000/89.2) showing an inhomogeneous area corresponding to the intrahepatic metastasis. The tumor with a size of 23 mm × 27 mm had a rapid growth compared with that before therapy.

Figure 3

Positive cell rate of mutant-type p53 protein in different groups.

Figure 4

Histological examination of VX2 tumor in different groups. A: immunohistochemical stain showing the low expression of mutant-type p53 gene high in VX2 cells in group B, magnification × 400, B: The same stain showing the expression in group D, (× 400).