1. ¹Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan
2. ²Department of Otolaryngology, Jichi Medical School, Tochigi, Japan
3. ³CREST, Japan Science and Technology Corporation (JST), Tochigi, Japan
4. ⁴Department of Anatomy, Jichi Medical School, Tochigi, Japan
5. ⁵Department of Otolaryngology, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
6. ⁶Department of Hematology, Jichi Medical School, Tochigi, Japan

Correspondence: K Ozawa, Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, 3311-1 Yakushiji Minamikawachi, Tochigi 329-0498, Japan

Received 15 January 2002; Accepted 10 June 2002.

Abstract

The application of adeno-associated virus (AAV) vectors to cancers is limited by their low transduction efficiency. Previously, we reported that -ray enhanced the second-strand synthesis, leading to the improvement of the transgene expression, and cytocidal effect of the herpes simplex virus type-1 thymidine kinase (HSVtk) and ganciclovir (GCV) system. In this study, we extended this in vitro findings to in vivo. First, the laryngeal cancer cell line (HEp-2) and HeLa were treated with AAVtk/GCV, the number of surviving cells was reduced as the concentration of GCV increased. Furthermore, the 4 Gy irradiation enhanced the killing effects of AAVtk/GCV by four-fold on HeLa cells and 15-fold on HEp-2 cells. Following the in vitro experiments, we evaluated the transgene expression and the antitumor activity of the AAV vectors in combination with -ray in nude mice inoculated with HEp-2 subcutaneously. The LacZ expression was observed in the xenografted tumors and significantly increased by -ray. The AAVtk/GCV system suppressed the tumors growth, and -ray augmented the antitumor activity by five-fold. These findings suggest that the combination of AAVtk/GCV system with radiotherapy is significantly effective in the treatment of cancers and may lead to reduction of the potential toxicity of both AAVtk/GCV and -ray.