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

✍ Scribed by Szilvia Desaknai; Katalin Lumniczky; Olga Esik; Hirofumi Hamada; Geza Safrany

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 147 KB
• Volume: 5
• Category: Article
• ISSN: 1099-498X
• DOI: 10.1002/jgm.357

✦ Synopsis

Abstract

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.

Conclusion

The combination of double‐suicide gene therapy with local irradiation is a promising tool to eradicate small, residual tumours. Copyright © 2002 John Wiley & Sons, Ltd.