Investigators took the enzyme that activates gemcitabine, deoxycytidine kinase (dCK) and inserted it into a viral carrier Ad-dCK. In vitro assay cells from mice, rats and humans, and mice infected with glioma (tumours originating from the spinal cord or brain) were then infiltrated with this gene therapy. Assay cells were subsequently treated with gemcitabine and irradiated. Tumour-bearing mice received an intraperitoneal injection of gemcitabine followed by local tumour irradiation. As gemcitabine is an anticancer agent with established efficacy, use of gene therapy to increase its enzymatic activation was hypothesised to offer potential improvements in chemo- and radiotherapy efficacy.
In vitro findings from the three different experimental glioma varied considerably. In the G1261 mouse cellular assay, increased levels of dCK enzyme activity failed to increase gemcitabine toxicity - although gemcitabine itself had a minor radiosensitising effect. Conversely, in rat C6 and 9L glioma cells, elevated dCK levels were found to substantially improve both gemcitabine toxicity and the radiosensitising effect.
Unsurprisingly, results from in vivo mouse studies mirrored the murine cellular assay findings. Although the combination of gemcitabine and radiotherapy had a pronounced synergistic effect, with 60% of animals tumour-free after 100 days compared to 0% on monotherapy, increased dCK levels did not impact on tumour growth or survival.
Experiments with C6 and 9L rat models are ongoing to further probe the promising increase in chemo- and radiosensitising effects of gemcitabine observed in response to elevated dCK levels. Ultimately, this gene the
Contact: Kirsten Mason
Federation of European Cancer Societies