Ionizing radiation activates late herpes simplex virus 1 promoters via the p38 pathway in tumors treated with oncolytic viruses

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 20; pp. 9479 - 9484
• Main Authors: MEZHIR, James J, ADVANI, Sunil J, SMITH, Kerrington D, DARGA, Thomas E, POON, Alice P. W, SCHMIDT, Hank, POSNER, Mitchell C, ROIZMAN, Bernard, WEICHSELBAUM, Ralph R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2005
• Subjects: Animals; Biological and medical sciences; Cercopithecus aethiops; Combined treatment; DNA, Viral - biosynthesis; DNA, Viral - genetics; Enzyme Activation; Gene Expression Regulation, Viral - radiation effects; HeLa Cells; Herpes simplex virus 1; Herpesvirus 1, Human - enzymology; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - radiation effects; Humans; MAP Kinase Signaling System; Medical sciences; Mice; Neoplasms - therapy; Neoplasms - virology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pancreatic Neoplasms - therapy; Pancreatic Neoplasms - virology; Phosphorylation; Promoter Regions, Genetic - radiation effects; Rabbits; Treatment. General aspects; Tumors; Up-Regulation - radiation effects; Vero Cells; Xenograft Model Antitumor Assays; Virus; Antineoplastic agent; Ionizing radiation; Treatment; Enzyme; Transcription promoter; Herpesviridae; Alphaherpesvirinae; Mitogen-activated protein kinase; Human herpesvirus 1; Malignant tumor; Oncolytic virus
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-1927

Ionizing radiation potentiates the oncolytic activity of attenuated herpes simplex viruses in tumors exposed to irradiation at specific time intervals by inducing higher virus yields. Cell culture studies have shown that an attenuated virus lacking the viral gamma(1)34.5 genes underproduces late proteins whose synthesis depends on sustained synthesis of viral DNA. Here we report that ionizing radiation enhances gene expression from late viral promoters in transduced cells in the absence of other viral gene products. Consistent with this result, we show that in tumors infected with the attenuated virus, ionizing radiation increases 13.6-fold above baseline the gene expression from a late viral promoter as early as 2 hours after virus infection, an interval too short to account for viral DNA synthesis. The radiation-dependent up-regulation of late viral genes is mediated by the p38 pathway, inasmuch as the enhancement is abolished by p38 inhibitors or a p38 dominant-negative construct. The p38 pathway is not essential for wild-type virus gene expression. The results suggest that ionizing radiation up-regulates late promoters active in the course of viral DNA synthesis and provide a rationale for use of radiation to up-regulate cytotoxic genes introduced into tumor cells by viral vectors for cytoreductive therapy.