Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines

Autor: Berchtold, Susanne, Beil, Julia, Raff, Christian, Smirnow, Irina, Schell, Martina, D’Alvise, Janina, Gross, Silvia, Lauer, Ulrich M.
Rok vydání: 2020
Předmět:
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 21, Iss 7618, p 7618 (2020)
Volume 21
Issue 20
ISSN: 1422-0067
Popis: 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 &ldquo
high-grade resistance&rdquo
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.
Databáze: OpenAIRE
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