1352 MICRORNA-MEDIATED TARGETING OF ONCOLYTIC HERPES SIMPLEX VIRUS-1 TO HIGH-RISK BLADDER CANCER (2011)

You have accessJournal of UrologyBladder Cancer: Basic Research1 Apr 20111352 MICRORNA-MEDIATED TARGETING OF ONCOLYTIC HERPES SIMPLEX VIRUS-1 TO HIGH-RISK BLADDER CANCER Yoshiyuki Matsui, Kevin Zhang, Cleo Lee, Lisa Skinner, Javad Banani, Alan So, Paul Rennie, and William Jia Yoshiyuki MatsuiYoshiyuki Matsui Kyoto, Japan More articles by this author , Kevin ZhangKevin Zhang Vancouver, Canada More articles by this author , Cleo LeeCleo Lee Vancouver, Canada More articles by this author , Lisa SkinnerLisa Skinner Vancouver, Canada More articles by this author , Javad BananiJavad Banani Vancouver, Canada More articles by this author , Alan SoAlan So Vancouver, Canada More articles by this author , Paul RenniePaul Rennie Vancouver, Canada More articles by this author , and William JiaWilliam Jia Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1174AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The results of current intravesical instillation therapy against high-grade non-muscle invasive bladder cancer (NMIBC) are unfortunately insufficient and, therefore, novel and safe intravesical options are absolutely required to prevent both recurrence and progression. Recent oncolytic virotherapy can offer a promising therapeutic option for treating such high-risk NMIBC, but the largest concern is to maintain tumor specificity of viral targeting without toxicity to normal organs. This study showed the effective tumor-specific targeting of intravesical instillation of oncolytic Herpes simplex virus (HSV)-1 using incorporating complementary target sequences of specific microRNAs (miRNAs). METHODS We examined expression levels of miRNA-124 and miRNA-143 in bladder cancer and normal bladder or various organs. Then we incorporated multiple copies of miRNA complementary target sequences (miRT) for miRNA-124, miRNA-143 or both into the 3′untranslated region (3′UTR) of a HSV-1 essential viral gene, ICP4, to create CMV-ICP4-124T, CMV-ICP4-143T and CMV-ICP4-124T-143T amplicon viruses and tested their targeting specificity and efficacy against bladder cancer, both in vitro and in vivo, using bladder cancer cell lines and mouse orthotopic bladder cancer xenograft model. RESULTS Our in vitro results have shown that all kinds of our viruses effectively inhibited bladder cancer proliferation but CMV-ICP4-143T-124T, which contains the combination of two miRT species, were much less toxic to neuronal cells. Our in vivo studies have also indicated that this plasmid is significantly safer than wild-type HSV-1 or other viruses with miRT for miRNA-124 or miRNA-143, both in nude and immunocompetent mice. When mice bearing tumors were treated with intravesical administration of viruses, a >80% reduction in tumor size and luciferase activity was observed in mice treated with this virus. Quantitative real-time PCR and immunohistochemical analyses of several organs showed very low levels of virus in only a few tissues in mice treated with CMV-ICP4-143T-124T, which was much less than that seen with other viral amplicons. CONCLUSIONS Our study is the first to demonstrate that inclusion of specific miRTs into an oncolytic HSV-1 virus is a promising strategy for high-grade NMIBC with restricting viral replication to bladder cancer cells while sparing normal cells. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e540 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshiyuki Matsui Kyoto, Japan More articles by this author Kevin Zhang Vancouver, Canada More articles by this author Cleo Lee Vancouver, Canada More articles by this author Lisa Skinner Vancouver, Canada More articles by this author Javad Banani Vancouver, Canada More articles by this author Alan So Vancouver, Canada More articles by this author Paul Rennie Vancouver, Canada More articles by this author William Jia Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...