Gamma-rays enhance rAAV-mediated transgene expression and cytocidal effect of AAV-HSVtk/ganciclovir on cancer cells.

Abstract

Adeno-associated virus (AAV) vector has several unique properties suited for gene therapy applications. However, relatively low efficiency of transgene expression, which is mainly due to a limited second-strand synthesis from the single-stranded AAV genome, can be a problem in some applications that require potent gene expression such as antitumor applications. Recently, gamma-ray irradiation has been reported to enhance the second-strand synthesis of the AAV genome, and consequently transgene expression. We demonstrate here that an AAV vector harboring the herpes simplex virus type-1 thymidine kinase (HSVtk) is able to kill cancer cells more efficiently when used in combination with gamma-ray irradiation. A human maxillary sinus cancer cell line, NKO-1, was efficiently killed in combination with HSVtk transduction and ganciclovir (GCV), as expected. More importantly, gamma-ray irradiation of practical dosages augmented the cytocidal effect of the HSVtk/GCV system. Southern analysis indicated that gamma-rays enhanced the double-strand synthesis of the rAAV genome in NKO-1 cells. These findings suggest that the combination of rAAVtk/GCV suicide gene therapy with radiotherapy has synergistic effects in the treatment of cancers and may lead to a reduction of the potential toxicity of both rAAVtk/GCV and gamma-ray irradiation.

• Authors: T Kanazawa, M Urabe, H Mizukami, T Okada, A Kume, H Nishino, J Monahan, K Kitamura, K Ichimura, K Ozawa
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 8 Issue 2 Pg. 99-106 (Feb 2001) ISSN: 0929-1903 [Print] England
• PMID: 11263531 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• DNA, Single-Stranded
• Thymidine Kinase
• Ganciclovir

Topics

• Antiviral Agents (pharmacology)
• Carcinoma, Squamous Cell (therapy, virology)
• DNA, Single-Stranded (metabolism)
• Dependovirus (genetics)
• Dose-Response Relationship, Radiation
• Gamma Rays
• Ganciclovir (pharmacology)
• Gene Expression (radiation effects)
• Genetic Therapy (methods)
• Genetic Vectors
• Herpesvirus 1, Human (enzymology)
• Humans
• Lac Operon
• Maxillary Sinus Neoplasms (therapy, virology)
• Radiation Dosage
• Survival Rate
• Thymidine Kinase (administration & dosage, genetics)
• Transgenes
• Tumor Cells, Cultured (drug effects)