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      A small interfering RNA targeting vascular endothelial growth factor efficiently inhibits growth of VX2 cells and VX2 tumor model of hepatocellular carcinoma in rabbit by transarterial embolization-mediated siRNA delivery

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          Abstract

          Introduction

          Hepatocellular carcinoma is currently the second leading cause of cancer-related deaths worldwide with an increasing incidence.

          Objective

          The objective of this study is to investigate the effect of vascular endothelial growth factor small interfering RNA (VEGF-siRNA) on rabbit VX2 carcinoma cell viability in vitro and the effect of transarterial embolization (TAE)-mediated VEGF-siRNA delivery on the growth of rabbit VX2 liver-transplanted model in vivo.

          Methods

          Quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot technologies were used to detect the expression level of VEGF. TAE and computed tomography scan were used to deliver the VEGF-siRNA and detect the tumor volume in vivo, respectively. Microvessel density was detected by immunohistochemistry with CD34 antibody. A biochemical autoanalyzer was used to evaluate the hepatic and renal toxicity.

          Results

          The designed VEGF-siRNAs could effectively decrease the expression levels of VEGF mRNA and protein in vitro and in vivo. In vitro, the viability of rabbit VX2 carcinoma cells was reduced by 38.5%±7.3% (VEGF-siRNA no 1) and 30.0%±5.8% (VEGF-siRNA no 3) at 48 hours after transfection. Moreover, in rabbit VX2 liver-transplanted model, the growth ratios of tumors at 28 days after TAE-mediated siRNA delivery were 155.18%±19.42% in the control group, 79.67%±19.63% in the low-dose group, and 36.09%±15.73% in the high-dose group, with significant differences among these three groups. Microvessel density dropped to 34.22±4.01 and 22.63±4.07 in the low-dose group and high-dose group, respectively, compared with the control group (57.88±5.67), with significant differences among these three groups. Furthermore, inoculation of VX2 tumor into the liver itself at later stage induced significant increase in alanine aminotransferase and aspartate aminotransferase, indicating an obvious damage of liver functions, while treatment of VX2 tumor via TAE-mediated VEGF-siRNA had no toxicity to the livers and kidneys of rabbits, and VEGF-siRNA had the ability to protect liver damage induced by tumor growth.

          Conclusion

          This is the first study to demonstrate that targeting VEGF via TAE-mediated siRNA delivery may become a powerful new option for effective treatment of hepatocellular carcinoma in the clinic.

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          Most cited references 47

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          Management of hepatocellular carcinoma.

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            siRNAs: applications in functional genomics and potential as therapeutics.

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              Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials.

              To review the available evidence of chemoembolization for unresectable hepatocellular carcinoma (HCC). Computerized bibliographic searches with MEDLINE and CANCERLIT databases from 1980 through 2000 were supplemented with manual searches, with the keywords "hepatocellular carcinoma," "liver cell carcinoma," "randomized controlled trial [RCT]," and "chemoembolization." Studies were included if patients with unresectable HCC were enrolled and if they were RCTs in which chemoembolization was compared with nonactive treatment (five RCTs) or if different transarterial modalities of therapy (13 RCTs) were compared. Data were extracted from each RCT according to the intention-to-treat method. Five of the RCTs with a nonactive treatment arm were combined by using the random-effects model, whereas all 18 RCTs were pooled from meta-regression analysis. Chemoembolization significantly reduced the overall 2-year mortality rate (odds ratio, 0.54; 95% CI: 0.33, 0.89; P =.015) compared with nonactive treatment. Analysis of comparative RCTs helped to predict that overall mortality was significantly lower in patients treated with transarterial embolization (TAE) than in those treated with transarterial chemotherapy (odds ratio, 0.72; 95% CI: 0.53, 0.98; P =.039) and that there is no evidence that transarterial chemoembolization is more effective than TAE (odds ratio, 1.007; 95% CI: 0.79, 1.27; P =.95), which suggests that the addition of an anticancer drug did not improve the therapeutic benefit. In patients with unresectable HCC, chemoembolization significantly improved the overall 2-year survival compared with nonactive treatment, but the magnitude of the benefit is relatively small.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                24 March 2016
                : 10
                : 1243-1255
                Affiliations
                [1 ]Department of Radiology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
                [2 ]Department of Radiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
                [3 ]Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
                [4 ]Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
                [5 ]Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
                [6 ]College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, People’s Republic of China
                [7 ]Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, People’s Republic of China
                Author notes
                Correspondence: Cai-Yun Fu, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, People’s Republic of China, Tel +86 571 8684 3336, Email fucy03@ 123456126.com
                Min-Ming Zhang, Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of China, Tel +86 571 8731 5255, Email zhangminming@ 123456zju.edu.cn
                Article
                dddt-10-1243
                10.2147/DDDT.S94122
                4818046
                27069355
                © 2016 Zou et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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