Abstract
Genetically modified vaccinia viruses (VACVs) have been shown to possess profound oncolytic capabilities. However, tumor cell resistance to VACVs may endanger broad clinical success. Using cell mass assays, viral replication studies, and fluorescence microscopy, we investigated primary resistance phenomena of cell lines of the NCI-60 tumor cell panel to GLV-1h94, a derivative of the Lister strain of VACV, which encodes the enzyme super cytosine deaminase (SCD) that converts the prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). After treatment with GLV-1h94 alone, only half of the cell lines were defined as highly susceptible to GLV-1h94-induced oncolysis. When adding 5-FC, 85% of the cell lines became highly susceptible to combinatorial treatment; none of the tested tumor cell lines exhibited a “high-grade resistance” pattern. Detailed investigation of the SCD prodrug system suggested that the cytotoxic effect of converted 5-FU is directed either against the cells or against the virus particles, depending on the balance between cell line-specific susceptibility to GLV-1h94-induced oncolysis and 5-FU sensitivity. The data provided by this work underline that cellular resistance against VACV-based virotherapy can be overcome by virus-encoded prodrug systems. Phase I/II clinical trials are recommended to further elucidate the enormous potential of this combination therapy.
Highlights
Cancer therapeutic resistance occurs as cancers develop resistance to treatments, such as chemotherapy, radiotherapy, and targeted therapies, through many different mechanisms
All 54 tumor cell lines were infected with GLV-1h94 at MOI 0.1 and tumor cell masses remaining at 96 h post infection were determined by a sulforhodamine B (SRB) assay
The potential of recombinant vaccinia virus GLV-1h94 was examined, which was designed to express super cytosine deaminase (SCD), a prodrug-converting enzyme encoded by the fcu1 gene [7]
Summary
Cancer therapeutic resistance occurs as cancers develop resistance to treatments, such as chemotherapy, radiotherapy, and targeted therapies, through many different mechanisms These include specific genetic and epigenetic changes in the cancer cell and/or the microenvironment in which the cancer cell resides. Oncolytic viruses (OVs) mediate their anti-tumoral effect both via a direct and an indirect mechanism of action. They selectively infect and replicate in tumor cells. OV-mediated cell death releases cytokines, tumor-associated antigens (TAAs), damage-associated molecular pattern molecules (DAMPs), and pathogen-associated molecular pattern molecules (PAMPs). These are taken up by antigen-presenting cells (APCs); in this course, CD4+ and CD8+ T cells are primed by cross-presentation. This activation of the adaptive immune system leads to an anti-tumoral immune response at tumor sites which have not been treated with virus [1,2]
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