title: Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging.
abstract: Hepatocellular carcinoma (HCC) is usually refractory to the available treatments. For cancer gene therapy purposes, real-time imaging of therapeutic gene expression is of great importance because there are multiple factors that modulate the therapeutic gene expression in a complex tumor microenvironment. As a consequence, multiple doses of therapeutic viral vectors may be required for improved efficacy. In the present study, the luciferase reporter gene and the yeast cytosine deaminase (yCD) genes were bicistronically expressed using the foot-and-mouth disease virus 2A peptide under the regulation of the cytomegalovirus (CMV) promoter. The effectiveness of the yCD/5-FC (5-fluorocytosine) killing efficacy mediated by the herpes simplex virus type 1 (HSV-1) amplicon viral vector was shown using HCC and non-HCC cell lines in vitro. In addition, in vivo experiment also showed tumor regression of a primary HCC 26-1004 tumor xenograft in tumor expressing high levels of the yCD gene (as determined by noninvasive imaging) after intratumoral injection of 1.5 × 10(6) TU HGCX-L2C HSV-1 amplicon viral vector and 5-FC administration. The HSV-1 amplicon viral vector coupled with the yCD/5-FC prodrug activated suicide gene could potentially be of use in clinical gene therapy for HCC.
authors.affiliation: Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: K C
authors.initials: KC
authors.lastname: Sia
authors.forename: H
authors.initials: H
authors.lastname: Huynh
authors.forename: N
authors.initials: N
authors.lastname: Chinnasamy
authors.forename: K M
authors.initials: KM
authors.lastname: Hui
authors.forename: P Y P
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics*; D005437:Flucytosine / Q000627:therapeutic use*; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics; D017930:Genes, Reporter; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D008156:Luciferases / Q000235:genetics; D008163:Luminescent Measurements / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D049452:Green Fluorescent Proteins; D005437:Flucytosine; D008156:Luciferases; D043525:Cytosine Deaminase