Document Detail


Concurrent chemotherapy inhibits herpes simplex virus-1 replication and oncolysis.
MedLine Citation:
PMID:  23348635     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Herpes simplex virus-1 (HSV-1) replication in cancer cells leads to their destruction (viral oncolysis) and has been under investigation as an experimental cancer therapy in clinical trials as single agents, and as combinations with chemotherapy. Cellular responses to chemotherapy modulate viral replication, but these interactions are poorly understood. To investigate the effect of chemotherapy on HSV-1 oncolysis, viral replication in cells exposed to 5-fluorouracil (5-FU), irinotecan (CPT-11), methotrexate (MTX) or a cytokine (tumor necrosis factor-α (TNF-α)) was examined. Exposure of colon and pancreatic cancer cells to 5-FU, CPT-11 or MTX in vitro significantly antagonizes both HSV-1 replication and lytic oncolysis. Nuclear factor-κB (NF-κB) activation is required for efficient viral replication, and experimental inhibition of this response with an IκBα dominant-negative repressor significantly antagonizes HSV-1 replication. Nonetheless, cells exposed to 5-FU, CPT-11, TNF-α or HSV-1 activate NF-κB. Cells exposed to MTX do not activate NF-κB, suggesting a possible role for NF-κB inhibition in the decreased viral replication observed following exposure to MTX. The role of eukaryotic initiation factor 2α (eIF-2α) dephosphorylation was examined; HSV-1-mediated eIF-2α dephosphorylation proceeds normally in HT29 cells exposed to 5-FU, CPT-11 or MTX. This report demonstrates that cellular responses to chemotherapeutic agents provide an unfavorable environment for HSV-1-mediated oncolysis, and these observations are relevant to the design of both preclinical and clinical studies of HSV-1 oncolysis.
Authors:
Y Kulu; H Kawasaki; J M Donahue; H Kasuya; J C Cusack; E W Choi; D K Kuruppu; B C Fuchs; K K Tanabe
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  Cancer gene therapy     Volume:  20     ISSN:  1476-5500     ISO Abbreviation:  Cancer Gene Ther.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-14     Completed Date:  2013-09-03     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9432230     Medline TA:  Cancer Gene Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  133-40     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Camptothecin / analogs & derivatives,  pharmacology
Cell Line, Tumor
Colonic Neoplasms / drug therapy*,  pathology,  virology
Combined Modality Therapy*
Fluorouracil / pharmacology
Herpesvirus 1, Human / genetics
Humans
Methotrexate / pharmacology
NF-kappa B / genetics,  metabolism
Oncolytic Virotherapy*
Oncolytic Viruses / genetics
Pancreatic Neoplasms / drug therapy*,  pathology,  virology
Transcriptional Activation / drug effects
Tumor Necrosis Factor-alpha / pharmacology
Virus Replication / drug effects,  genetics
Grant Support
ID/Acronym/Agency:
CA077278/CA/NCI NIH HHS; CA64454/CA/NCI NIH HHS; CA71345/CA/NCI NIH HHS; CA76183/CA/NCI NIH HHS; DK43352/DK/NIDDK NIH HHS; K08 CA077278/CA/NCI NIH HHS; R01 CA076183/CA/NCI NIH HHS; R29 CA064454/CA/NCI NIH HHS; T32 CA071345/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/NF-kappa B; 0/Tumor Necrosis Factor-alpha; 7673326042/irinotecan; U3P01618RT/Fluorouracil; XT3Z54Z28A/Camptothecin; YL5FZ2Y5U1/Methotrexate
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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