title: Combinatorial strategies based on CRAd-IL24 and CRAd-ING4 virotherapy with anti-angiogenesis treatment for ovarian cancer.
abstract: BACKGROUND
  A major hurdle incurrent to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy agents is their limited therapeutic efficacy. In this study we evaluated whether arming our previously reported Ad5/3Δ24 CRAd vector containing a 24-base pair deletion in the E1A conserved region 2, which allows selective replication within Rb-p16-deficient tumor cells, to express therapeutic genes could improve oncolytic virus potency in ovarian cancer cells. We choose to assess the therapeutic benefits achieved by virus-mediated expression of interleukin 24 (IL-24), a cytokine-like protein of the IL-10 family, and the inhibitor of growth 4 (ING4) tumor suppressor protein.
  
  
  RESULTS
  The generated CRAd-IL24 and CRAd-ING4 vectors were tested in ovarian cancer cell lines in vitro to compare their replication, yield, and cytotoxic effects with control CRAd Ad5/3∆24 lacking the therapeutic gene. These studies showed that CRAd-IL24 infection resulted in significantly increased yield of infectious particles, which translated to a marked enhancement of virus-induced cytotoxic effects as compared to CRAd-ING4 and non-armed CRAd. Testing CRAd-IL24 and CRAd-ING4 vectors combined together did not revealed synergistic effects exceeding oncolytic potency of single CRAD-IL24 vector. Both CRAds were also tested along with anti-VEGF monoclonal antibody Avastin and showed no significant augmentation of viral cytolysis by anti-angiogenesis treatment in vitro.
  
  
  CONCLUSIONS
  Our studies validated that arming with these key immunomodulatory genes was not deleterious to virus-mediated oncolysis. These findings thus, warrant further preclinical studies of CRAd-IL24 tumoricidal efficacy in murine ovarian cancer models to establish its potential utility for the virotherapy of primary and advanced neoplastic diseases.
authors.affiliation: Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, PO Box 7607, Holy Makkah, Saudi Arabia.
authors.forename: Ahmad Mohammad
authors.initials: AM
authors.lastname: Ashshi
authors.affiliation: Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, PO Box 7607, Holy Makkah, Saudi Arabia.|Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Adel Galal
authors.initials: AG
authors.lastname: El-Shemi
authors.affiliation: The Division of Cancer Biology and Biologic Therapeutic Center, Department of Radiation Oncology, School of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8224, St. Louis, MO, 63110, USA.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.affiliation: The Division of Cancer Biology and Biologic Therapeutic Center, Department of Radiation Oncology, School of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8224, St. Louis, MO, 63110, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Kashentseva
authors.affiliation: The Division of Cancer Biology and Biologic Therapeutic Center, Department of Radiation Oncology, School of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8224, St. Louis, MO, 63110, USA. dcuriel@radonc.wustl.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000068258:Bevacizumab / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D023061:Gene Order; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014779:Virus Replication; D000099180:Interleukin-24
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D007378:Interleukins; D025521:Tumor Suppressor Proteins; D000099180:Interleukin-24; C483230:ING4 protein, human
keywords: Adenovirus; CRAd; IL-24; ING4; Ovarian cancer; Virotherapy