Local tumour irradiation enhances the anti-tumour effect of a double-suicide gene therapy system in a murine glioma model.

Abstract

Gliomas are invasive malignant tumours with poor prognosis. Combination of gene directed enzyme pro-drug therapy with existing treatment modalities might open new therapeutic potentials. Murine glioma 261 (Gl261) cells were transduced with an adenoviral vector (Adex-CAUPTK) encoding both uracil phosphoribosyltransferase and thymidine kinase genes which sensitise cells to 5-fluorouracil (5-FU) and ganciclovir (GC), respectively. Subcutaneous or intracranial tumours were established in C57Bl mice by transplanting drug-sensitising gene containing Gl261 cells. In vitro growing cells or established tumours were treated with 5-FU, GC and ionising radiation either alone or in combinations. Finally, subcutaneous tumours were established with non-transduced cells, directly injected with Adex-CAUPTK, and mice were treated with combinations of 5-FU, GC and tumour irradiation. In vitro treatment of transduced Gl261 cells with both 5-FU and GC showed enhanced cytotoxic effect compared with single agents. Combination of drug treatments with irradiation greatly increased cytotoxicity. In subcutaneous and intracranial tumours double-agent treatment was more effective than a single drug. Combination with local irradiation highly improved the anti-tumour effect (90-100% survival) even when only part of the tumour cells carried drug-sensitising genes (40-50% survival at 10% rate). Treatment of established tumours with direct intra-tumour Adex-CAUPTK inoculations and intraperitoneal 5-FU, GC injections slowed down tumour progression that was further enhanced by local irradiation. The combination of double-suicide gene therapy with local irradiation is a promising tool to eradicate small, residual tumours.