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

International Journal of Molecular Sciences

Janina D’Alvise¹  Christian Raff²  Silvia Gross²  Susanne Berchtold²  Martina Schell²  UlrichM. Lauer²  Julia Beil²  Irina Smirnow² 

[1] Core Facility for Medical Bioanalytics, Institute for Ophthalmic Research, University Hospital Tübingen, D-72076 Tübingen, Germany;Department of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, Germany;

关键词: oncolytic virotherapy;    virotherapy resistance;    vaccinia virus;    NCI-60 tumor cell panel;    super cytosine deaminase prodrug system;    chemovirotherapy;   

DOI  :  10.3390/ijms21207618

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown