Gene therapy improves gemcitabine effects in experimental glioma model

October 31, 2005

Paris, France, Monday 31 October 2005 - Attempts to improve the chemotherapeutic efficacy and radiotherapy-sensitivity of the anticancer agent, gemcitabine, using gene therapy have yielded interesting results in preclinical glioma models presented at the 13th European Cancer Conference (ECCO).

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 therapy approach may open up avenues to increase the overall efficacy of chemotherapy and radiotherapy.

Speaking at ECCO 13, study author, Dr Katalin Lumniczky from the National Research Institute for Radiobiology, Budapest commented, "These results highlight the important and increasing role that gene therapy will hold for treatments in the future. Radiotherapy along with surgery, is the main therapeutic strategy in the treatment of most cancers. Our research aims to selectively increase radiosensitivity of tumour cells by the means of gene therapy. In this way tumour cells could respond better to conventional doses of radiation, resulting in higher tumour cell kill. This might have two main impacts on the patient. Firstly, patients having a radio-resistant tumour could be treated more successfully without the need to increase radiation doses. Secondly, it would even make it possible to reduce radiation doses in those patients whose normal tissues are known to be more radiosensitive than normal, and who, by this are at a high risk of developing long lasting side-effects after radiation which can substantially reduce their quality of life. Essentially, our research could help both in improving the success rate of radiotherapy and in reducing undesired side-effects."

About Gliomas

Half of all primary brain tumours (those originating from the brain and not from other parts of the body) are classified as gliomas. A glioma refers to a brain tumour that begins in glial, or supportive cells of the brain or spinal cord. There are four types of gliomas, astrocytoma, ependymoma and oligodendroglioma and mixed glioma (mixture of the other types).

The most common type are astrocytomas which develop from cells called astrocytes (type of cell that supports neurones). As with all types of gliomas, they are classified as either high grade or low grade. High grade tumours are malignant and difficult to treat whereas low grade tumours are slow growing and treatable.1

Unlike other cancers, the geographical incidence of brain tumours should be cautiously interpreted as the criteria and registration of brain tumours is not always consistent. However, the incidence does rise from the age of thirty, with males more likely to be diagnosed with gliomas than females with a ratio of 1.5:1.2

The causes of gliomas are largely unknown. By studying large numbers of patients, researchers have found certain risk factors that increase a person's chance of developing gliomas . Some studies have shown that working in certain industries increases a person's susceptibility to a glioma. Researchers are currently looking into the possibility of exposure to viruses as another possible cause and some scientists are investigating whether it might be hereditary. 3

Treatment options include surgery, radiotherapy and chemotherapy. Recently, there are a number of new anti-cancer treatments such as the anti-metabolites (interfere with the growth of cancer cells) e.g. gemcitabine, currently in clinical trials for possible treatment of gliomas.4
2 McKinney, P.A. Brain Tumours: Incidence, Survival, and Aetiology. Journal of Neurology, Neruosurgery and Psychiatry. 2004;75:ii12
4 Medline Plus Drug Information

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Abstract: 514
301 Central nervous system
Combined treatment of experimental gliomas with radiotherapy, radiosensitizing and chemosensitizing gene therapy
K. Lumniczky1, T. Szatmari1, G. Huszty1, S. Desaknai1, M. Sasvari-Szekely2, M. Staub2, G. Safrany1
1NCPH - National Research Institute for Radiobiolog, Molecular and Tumour Radiobiology, Budapest, Hungary
2Semmelweis University, Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Budapest, Hungary
The aim of this work was to improve the chemotherapeutic and radiosensitising effects of gemcitabine. Our hypothesis was that increasing the deoxycytidine kinase (dCK) enzyme level that activates gemcitabine within the cells, will lead to increased gemcitabine effects, which could improve the efficacy of chemo- and radiotherapy.
Material and methods:
Murine Gl261, rat C6 and 9L and human U373 glioma models were used. The dCK gene was cloned into an adenoviral vector (Ad-dCK). For in vitro proliferation assay cells were transduced with Ad-dCK, treated with Gemcitabine and irradiated. Subcutaneous Gl261 tumours were established in C57BL/6 mice using either wild type or Ad-dCK infected tumour cells. Tumour bearing mice were treated with intraperitoneal injection of Gemcitabine and local tumour irradiation. Tumour growth and survival were followed.
Strong differences were seen in the basal dCK activities of the different glioma cell lines: the murine Gl261 cells showed ten fold higher enzyme activities, than the human and rat glioma cell lines. Intracellular dCK activity was raised by infecting the cells with increasing multiplicities of infection (MOI) of Ad-dCK. Ad-dCK at high MOI was very toxic for Gl261 cells, but did not affect the viability of the other glioma cell lines. The in vitro data showed that increased dCK enzyme activities could not further increase gemcitabine toxicity in Gl261 cells, but gemcitabine itself had a minor radiosensitizing effect. On the contrary, in rat C6 and 9L glioma cells elevated dCK levels could substantially improve both gemcitabine toxicity and the radiosensitising effect. In the case of Gl261 cells, in vivo data are in concordance with the in vitro data: although the combined effect of gemcitabine and radiotherapy has a pronounced synergistic effect (60% tumour free animals after 100 days) compared to mono-therapies (no tumour free animals), increasing dCK levels in the tumour cells did not affect tumour growth or survival. Experiments with C6 and 9L rat models are undergoing.
In the Gl261 model increasing intracellular dCK levels could not improve the chemo- or radio-sensitizing effect of gemcitabine. In the C6 and 9L models elevated dCK levels could increase both the chemo- and radio-sensitizing effect of gemcitabine.

ECCO-the European CanCer Organisation

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