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


METHODS
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.


RESULTS
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.


CONCLUSIONS
The combination of double-suicide gene therapy with local irradiation is a promising tool to eradicate small, residual tumours.
Department of Molecular and Tumour Radiobiology, National Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary.
Szilvia
S
Desaknai
Katalin
K
Lumniczky
Olga
O
Esik
Hirofumi
H
Hamada
Geza
G
Safrany
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000532:radiotherapy* / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000532:radiotherapy* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011878:Radiotherapy / Q000379:methods; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D015774:Ganciclovir; D005472:Fluorouracil