Molecular engineering and validation of an oncolytic herpes simplex virus type 1 transcriptionally targeted to midkine-positive tumors
| Autor: | Timothy M. Crombleholme, Bruce J. Aronow, Timothy P. Cripe, Arturo R. Maldonado, Anil G. Jegga, Yonatan Y. Mahller, Chuck Klanke |
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| Rok vydání: | 2010 |
| Předmět: |
Cytotoxicity
Immunologic Transcription Genetic Mice Nude Herpesvirus 1 Human Virus Replication medicine.disease_cause Nerve Sheath Neoplasms Virus Mice In vivo Cell Line Tumor Drug Discovery Genetics medicine Animals Humans Nerve Growth Factors Transgenes RNA Small Interfering Luciferases Molecular Biology Genetics (clinical) Cell Proliferation Oncolytic Virotherapy Midkine biology Cell growth Survival Analysis Xenograft Model Antitumor Assays Molecular biology Oncolytic virus Oncolytic Viruses Cell Transformation Neoplastic Herpes simplex virus Viral replication Cell culture Gene Knockdown Techniques biology.protein Molecular Medicine Female Genetic Engineering |
| Zdroj: | The Journal of Gene Medicine. 12:613-623 |
| ISSN: | 1521-2254 1099-498X |
| DOI: | 10.1002/jgm.1479 |
| Popis: | 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, γ134.5, 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. Copyright © 2010 John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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