Engineering Viruses that Only Replicate in Cancer Cells

One of the many interesting approaches to targeting cancer cells for destruction is the use of viruses that are largely innocuous to humans, but replicate preferentially in cells exhibiting the characteristics of cancer, such as continual cellular replication. Researchers here demonstrate a way to engineer a virus to require the biochemistry of cell replication for it to also replicate, ensuring that it will affect only cancerous tissue.

Much research in recent years has investigated genetically modifying adenoviruses to kill cancers, with some currently being tested in clinical trials. When injected, these adenoviruses replicate inside cancer cells and kill them. Scientists are trying to design more efficient viruses, which are better able to target cancer cells while leaving normal cells alone. Researchers have now made two new adenoviruses that specifically target cancer cells. To do this, they used adenylate-uridylate-rich elements (AREs), which are signals in RNA molecules known to enhance the rapid decay of messenger RNAs (mRNAs) in human cells. AREs make sure that mRNAs don't continue to code for proteins unnecessarily in cells. Genes required for cell growth and proliferation tend to have AREs.

Under certain stress conditions, however, ARE-containing mRNAs can become temporarily stabilized allowing the maintenance of some necessary cell processes. ARE-mRNAs are also stabilized in cancer cells, supporting their continuous proliferation. Researchers inserted AREs from two human genes into an adenovirus replicating gene, making the new adenoviruses: AdARET and AdAREF. AdARET and AdAREF were both found to replicate inside and kill cancer cells in the laboratory, while they hardly affected normal cells. Tests confirmed that the specific replication in cancer cells was due to stabilization of the viral genes with AREs, which did not happen in the healthy cells. The scientists then injected human cancer cells under the skin of nude mice, which then developed into tumors. When AdARET and AdAREF were injected into the tumors, they resulted in a significant reduction in tumor size.


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