Vascular damage and anti-angiogenic effects of tumor vessel-targeted adenovirus-mediated herpes simplex virus thymidine kinase gene

Abstract

RESULTS:Immunocytochemical staining indicated the expression of KDR antigen in HUVEC. Under adenovirus infection index of 100, with increasing GCV concentration from 0 up to 50 mg/L, the survival rate of AdKDR-tktransfected HUVEC and HepG2 decreased from 100% to (28.94 ± 5.67)% and (75.45 ± 2.91)% at proper order, respectively (P < 0.01), while the survival rate of AdCMVtk-transfected HUVEC and HepG2 declined from 100% to (17.56 ± 2.48)% and (23.15 ± 5.72)%, respectively (P > 0.05). Compared with groupⅠ, there was a decrease of tumor weight by 14.7% in group Ⅲ and by 23.6% in group Ⅳ. And there was a distinct difference between group Ⅲ and Ⅳ (P < 0.05). The median MVD for all groups was 37.4 ± 8.6, 30.6 ± 7.8, 27.6 ± 7.1, and 10.7 ± 4.1 (microvessels/mm 2 ) in groupⅠ, Ⅱ, Ⅲ and Ⅳ, respectively. And there was a marked difference between group Ⅲ and Ⅱ (P < 0.05), Ⅳ and Ⅱ (P < 0.01), and Ⅳ and Ⅲ (P < 0.01). CONCLUSION: INTRODUCTIONHepatocellular carcinoma (HCC) is the third leading cause of cancer death, with over a million new cases annually [1] . Because the success of the conventional therapies is limited, Gene and immunotherapy using a variety of strategies are in development at present. HCC possesses several characteristics that make it an attractive target for these therapies [2,3] .

Transcriptional targeting of tumor endothelial cells for gene therapy

“…As mentioned above, delivery of HSV-TK gene by recombinant retrovirus to endothelial cells of xenograft tumor under the control of PPET-1 promoter followed by administration of ganciclovir resulted in widespread vascular disruption and tumor cell apoptosis [124]. It was reported that in situ administration of recombinant adenovirus expressing the HSV-TK gene under VEGFR-2 promoter regulation inhibited tumor vascularization, and reduced tumor volume in a xenograft tumor model of hepatocellular carcinoma [156]. …”

Suicide Gene Therapy by Herpes Simplex Virus-1 Thymidine Kinase (HSV-TK)

“…Upon treatment with GCV, undifferentiated cells die but differentiated cells are free from harm [60]. Combination gene therapy using multidrug resistance (MDR1) shRNA and HPV-TK [61], targeting angiogenesis of hepatocellular carcinoma with GCV treatment has been done [62]. Transfection of wild type p53 makes C6 glioma cells more susceptible to GCV treatment [63].…”