Targeted oncolytic herpes simplex virus type 1 eradicates experimental pancreatic tumors
| Autor: | Alberto L. Epstein, Naïma Hanoun, Coline Biollay, Hubert Lulka, Jean-Luc Béjot, Louis Buscail, Alix Vignolle-Vidoni, Pierre Cordelier, Pascal Trempat, Herve Berthomme, Marion Gayral, Janick Selves |
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| Rok vydání: | 2014 |
| Předmět: |
Pathology
medicine.medical_specialty Mice Nude Antineoplastic Agents Apoptosis Cell Cycle Proteins Herpesvirus 1 Human Biology Injections Intralesional medicine.disease_cause Deoxycytidine Virus Mice Viral Proteins Cell Line Tumor Genetics medicine Animals Humans Promoter Regions Genetic Molecular Biology Pancreas Research Articles Oncolytic Virotherapy Gemcitabine Oncolytic virus Tumor Burden Pancreatic Neoplasms Disease Models Animal Herpes simplex virus Viral replication Gene Expression Regulation Tumor progression Cancer cell Trans-Activators Molecular Medicine Tumor necrosis factor alpha Genetic Engineering Neoplasm Transplantation Carcinoma Pancreatic Ductal |
| Zdroj: | Human gene therapy. 26(2) |
| ISSN: | 1557-7422 |
| Popis: | As many other cancers, pancreatic ductal adenocarcinoma (PDAC) progression is associated with a series of hallmark changes for cancer cells to secure their own growth success. Yet, these very changes render cancer cells highly sensitive to viral infection. A promising strategy may rely on and exploit viral replication for tumor destruction, whereby infection of tumor cells by a replication-conditional virus may lead to cell destruction and simultaneous release of progeny particles that can spread and infect adjacent tumor cells, while sparing healthy tissues. In the present study, we used Myb34.5, a second-generation replication-conditional herpes simplex virus type 1 (HSV-1) mutant in which ICP6 gene expression is defective and expression of the HSV-1 γ134.5 gene is regulated by the cellular B-myb promoter. We found that B-myb is present in experimental PDAC and tumors, and is overexpressed in patients' tumors, as compared with normal adjacent pancreas. Myb34.5 replicates to high level in human PDAC cell lines and is associated with cell death by apoptosis. In experimental models of PDAC, mice receiving intratumoral Myb34.5 injections appeared healthy and tumor progression was inhibited, with evidence of tumor necrosis, hemorrhage, viral replication, and cancer cell death by apoptosis. Combining standard-of-care chemotherapy with Myb34.5 successfully led to a very impressive antitumoral effect that is rarely achieved in this experimental model, and resulted in a greater reduction in tumor growth than chemotherapy alone. These promising results warrant further evaluation in early phase clinical trial for patients diagnosed with PDAC for whom no effective treatment is available. |
| Databáze: | OpenAIRE |
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