Tumor-targeted gene therapy using Adv-AFP-HRPC/IAA prodrug system suppresses growth of hepatoma xenografted in mice

State Key Laboratory of Virology, School of Basic Medicine, Wuhan University, Wuhan, People's Republic of China.
Cancer gene therapy (Impact Factor: 2.42). 09/2011; 19(2):77-83. DOI: 10.1038/cgt.2011.65
Source: PubMed


Clinical efficacy of current therapies for hepatocellular carcinoma (HCC) treatment is limited. Indole-3-acetic acid (IAA) is non-toxic for mammalian cells. Oxidative decarboxylation of IAA by horseradish peroxidase (HRP) leads to toxic effects of IAA. The purpose of this study was to investigate the effects of a novel gene-targeted enzyme prodrug therapy with IAA on hepatoma growth in vitro and in vivo mouse hepatoma models. We generated a plasmid using adenovirus to express HRP isoenzyme C (HRPC) with the HCC marker, alpha-fetoprotein (AFP), as the promoter (pAdv-AFP-HRPC). Hepatocellular cells were infected with pAdv-AFP-HRPC and treated with IAA. Cell death was detected using MTT assay. Hepatoma xenografts were developed in mice by injection of mouse hepatoma cells. The size and weight of tumors and organs were evaluated. Cell death in tumors was assessed using hematoxylin and eosin-stained tissue sections. HRPC expression in tissues was detected using Reverse Transcriptase-Polymerase Chain Reaction. IAA stimulated death of hepatocellular cells infected with pAdv-AFP-HRPC, in a dose- and time-dependent manner, but not in control cells. Growth of hepatoma xenografts, including the size and weight, was inhibited in mice treated with pAdv-AFP-HRPC and IAA, compared with that in control group. pAdv-AFP-HRPC/IAA treatment induced cell death in hepatoma xenografts in mice. HRPC gene expressed only in hepatoma, but not in other normal organs of mice. pAdv-AFP-HRPC/IAA treatment did not cause any side effects on normal organs. These findings suggest that pAdv-AFP-HRPC/IAA enzyme/prodrug system may serve as a strategy for HCC therapy.

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    • "Based on the views that formation of enzyme-substrate complexes such as [POX-IAA-O2] results in release of O•−2 (Kawano et al., 2001), medical application of HRP-labeled antibodies and IAA has been proposed as a novel O•−2-generating system for cancer cell-targeted and controlled cell death induction, by designing the HRP-conjugated immuno-labeling of cancer-related molecules or expression of recombinant HRP in mammalian cells (Folkes and Wardman, 2001; Folkes et al., 2002; Kawano, 2003b; Dai et al., 2012). Although the IAA-induced O•−2 in HRP reaction mixture is very intense, the IAA-induced oxidative burst likely lasts only for few seconds (Kawano et al., 2001). "
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