27 October 2020
Trojan attack on tumour cells
Published online 14 January 2011
The targeted killing of cancerous cells is the goal of chemotherapy. Gene therapy is being used to selectively insert genes into tumour cells that tear them apart from the inside while leaving normal tissue unscathed.
An international team of researchers has exploited the fact that the transcription factor NF-κB, a nuclear signaling protein triggered by extracellular stresses, is highly active in tumour cells.
They designed a virus to enter tumour cells and use NF-κB to drive the expression of two yeast enzymes, cytosine deaminase and uracil phosphoribosyltransferase (CU). Cells that express this fusion protein convert the prodrug 5-FU into a toxin that is deadly to the cell.
This gene-directed enzyme/prodrug strategy included an innovative way to monitor the success of cell transformation: the researchers attached a gene for Gaussia Luciferase (Gluc), an enzyme that catalyzes a reaction that emits light, enabling researchers to monitor the level of transgene expression using a simple blood assay. This offers a practical way to monitor transgene expression in humans.
Tests in several tumour cell lines, including lung and prostate adenocarcinomas, resulted in a 50% decrease in cell viability. Treated tumours in mice that received both 5-FC and TNF-a, a cytokine that boosts NF-κB activity, regressed within 2 weeks and completely disappeared in 40% of mice.
The researchers suggest that refining their approach, possibly by testing various ways to deliver these 'suicide' genes, could enhance the cellular killing effect of the therapy and enable researchers to test different gene/drug therapies.
- Badr, CE. et al. Suicidal gene therapy in an NF-κB-controlled tumor environment as monitored by a secreted blood reporter. Gene Therapy. 9 September 2010. doi: 10.1038/gt.2010.156