RRC ID 6862
Author Maldonado AR, Klanke C, Jegga AG, Aronow BJ, Mahller YY, Cripe TP, Crombleholme TM.
Title Molecular engineering and validation of an oncolytic herpes simplex virus type 1 transcriptionally targeted to midkine-positive tumors.
Journal J Gene Med
Abstract BACKGROUND:Expression profile analyses of midkine (MDK), a multifunctional protein important in development but repressed postnataly, indicate that it is highly expressed in approximately 80% of adult carcinomas and many childhood cancers including malignant peripheral nerve sheath tumors (MPNST). In the present study, we sought to leverage its selective expression to develop a novel oncolytic herpes simplex virus (oHSV) capable of targeting developmentally primitive cancers that express MDK.
METHODS:We sought to increase the oncolytic efficacy of the virus by fusing the human MDK promoter to the HSV type 1 neurovirulence gene, gamma(1)34.5, whose protein product increases viral replication.
RESULTS:Tissue-specific MDK promoter activity in human tumor cells and transgene biological activity was confirmed in human MPNST tumor cells. In vitro replication and cytotoxicity in human fibroblasts and MPNST cells by plaque and MTT assays showed that oHSV-MDK-34.5 increased replication and cytotoxicity compared to oHSV-MDK-Luc. By contrast, no significant difference in cytotoxicity was detected between these viruses in normal human fibroblasts. oHSV-MDK-34.5 impaired in vivo tumor growth and increased median survival of MPNST tumor-bearing nude mice.
CONCLUSIONS:The transcriptional targeting of HSV lytic infection to MDK-expressing tumor cells is feasible. oHSV-MDK-34.5 shows enhanced anti-tumor effects both in vitro and in vivo. Further studies are warranted and may lead to its use in clinical trials.
Volume 12(7)
Pages 613-23
Published 2010-7
DOI 10.1002/jgm.1479
PMID 20603890
MeSH Animals Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic / pathology Cytotoxicity, Immunologic Female Gene Knockdown Techniques Genetic Engineering / methods* Herpesvirus 1, Human / genetics* Herpesvirus 1, Human / physiology Humans Luciferases / genetics Mice Mice, Nude Nerve Growth Factors / metabolism* Nerve Sheath Neoplasms / genetics Nerve Sheath Neoplasms / therapy* Oncolytic Virotherapy / methods* Oncolytic Viruses / genetics* Oncolytic Viruses / physiology RNA, Small Interfering / metabolism Survival Analysis Transcription, Genetic* Transgenes / genetics Virus Replication / physiology Xenograft Model Antitumor Assays
IF 1.647
Times Cited 10
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL BIOTECHNOLOGY & APPLIED MICROBIOLOGY GENETICS & HEREDITY
Resource
DNA material pKM2L-phMK (RDB05514)