期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 34, 页码 12873-12878出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0605496103
关键词
gene therapy; innate immunity; oncolytic virus; brain tumor; herpes simplex virus
资金
- NCI NIH HHS [P30 CA016058, P01 CA69246, CA95426, R01 CA085139, R37 CA068458, P01 CA095426, CA16058, P01 CA069246, CA68458, R01 CA068458, R01 CA85139] Funding Source: Medline
- NINDS NIH HHS [R01 NS041571, NS41571] Funding Source: Medline
Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/ macrophages (CD68(+) and CD163(+)), and IFN-gamma. Pretreatment with CPA enhances HSV replication and oncolysis and reduces an HSV-mediated increase in CD68(+) and CD163+ cells and intratumoral IFN-gamma. Molecular imaging shows CPA pretreatment to inhibit HSV-induced infiltration of tumor-associated phagocytic cells. Our results reveal molecular and cellular mechanisms that inhibit intratumoral spread of HSV and suggest a therapeutic path for improving the efficacy of virotherapy as a treatment for cancer.
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