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Targeting Nucleotide Biosynthesis: A Strategy for Improving the Oncolytic Potential of DNA Viruses
Chad R Irwin1,2, Mary M Hitt2,3, David H Evans1,2
1Faculty of Medicine and Dentistry, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
Abstract:
The rapid growth of tumors depends upon elevated levels of dNTPs, and while dNTP concentrations are tightly regulated in normal cells, this control is often lost in transformed cells. This feature of cancer cells has been used to advantage to develop oncolytic DNA viruses. DNA viruses employ many different mechanisms to increase dNTP levels in infected cells, because the low concentration of dNTPs found in non-cycling cells can inhibit virus replication. By disrupting the virus-encoded gene(s) that normally promote dNTP biosynthesis, one can assemble oncolytic versions of these agents that replicate selectively in cancer cells. This review covers the pathways involved in dNTP production, how they are dysregulated in cancer cells, and the various approaches that have been used to exploit this biology to improve the tumor specificity of oncolytic viruses. In particular, we compare and contrast the ways that the different types of oncolytic virus candidates can directly modulate these processes. We limit our review to the large DNA viruses that naturally encode homologs of the cellular enzymes that catalyze dNTP biogenesis. Lastly, we consider how this knowledge might guide future development of oncolytic viruses.
Insights
Cancer cells often have high deoxyribonucleotide triphosphate (dNTP) levels, which oncolytic DNA viruses exploit. Disrupting viral genes that promote dNTP synthesis creates tumor-specific viruses.
Area of Science:
- Virology
- Cancer Biology
- Molecular Oncology
Background:
- Tumor growth relies on elevated deoxyribonucleotide triphosphate (dNTP) levels, a control often lost in cancer cells.
- Normal cells tightly regulate dNTP concentrations, while cancer cells exhibit dysregulated dNTP pools.
- Low dNTP levels in non-cycling cells can impede DNA virus replication.
Purpose of the Study:
- To review pathways of dNTP production and their dysregulation in cancer.
- To explore strategies for developing tumor-specific oncolytic DNA viruses.
- To compare how different oncolytic virus candidates modulate dNTP biosynthesis.
Main Methods:
- Review of scientific literature on dNTP metabolism and oncolytic virus development.
- Analysis of mechanisms employed by large DNA viruses to increase intracellular dNTP levels.
- Comparison of viral strategies targeting dNTP biosynthesis pathways.
Main Results:
- Cancer cells exhibit altered dNTP regulation, creating a vulnerability for oncolytic viruses.
- Oncolytic DNA viruses utilize diverse mechanisms to enhance dNTP pools for replication.
- Disrupting viral genes involved in dNTP synthesis can yield tumor-selective oncolytic agents.
Conclusions:
- Exploiting cancer-specific dNTP dysregulation is a key strategy for enhancing oncolytic virus tumor specificity.
- Large DNA viruses encoding homologs of cellular dNTP biosynthesis enzymes offer promising platforms.
- Understanding dNTP metabolism can guide future oncolytic virus design and optimization.
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