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Enhanced antitumor effect and reduced vector dissemination with fiber-modified adenovirus vectors expressing herpes simplex virus thymidine kinase

Cancer Gene Therapy volume 9, pages 236–242 (2002)Cite this article

Abstract

There are at least two hurdles confronting the use of the adenovirus (Ad)-mediated herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system for the treatment of cancer. One is inefficient Ad vector–mediated gene transfer into tumor cells lacking the primary receptor, i.e., the coxsackievirus and adenovirus receptor (CAR). The other is hepatotoxicity due to unwanted vector spread into the liver, even when Ad vectors are injected intratumorally. Herein, we present an attractive strategy for overcoming such limitations based on use of a fiber-modified Ad vector containing an RGD peptide motif in the fiber knob. HSVtk-expressing Ad vectors containing mutant fiber (AdRGD-tk) or wild-type fiber (Ad-tk) were injected intratumorally into CAR-negative B16 melanoma cells inoculated into mice, after which GCV was injected intraperitoneally for 10 days. AdRGD-tk showed approximately 25 times more antitumor activity than Ad-tk. Histopathological studies suggested that liver damage in mice injected with AdRGD-tk was significantly lower than that in mice injected with Ad-tk. Intratumoral administration of luciferase-expressing Ad vectors containing the mutant fiber (AdRGD-L2) resulted in nearly 40 times more luciferase production in the tumor, but 8 times less production in the liver than the conventional Ad vectors (Ad-L2). These results indicate that combination of fiber-modified vectors and a HSVtk/GCV system is a potentially useful and safe approach for the treatment of tumors lacking CAR expression, and that fiber-modified vectors could be of great utility for gene therapy and gene transfer experiments.

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Acknowledgements

We thank Jun Murai and Nobuko Heishi for their technical assistance. We also thank Dr Akiyoshi Nishikawa (National Institute of Health Sciences, Tokyo, Japan) for his helpful discussion about histological study. This work was supported by grants from the Ministry of Health, Labour, and Welfare of Japan and a Grant-in-Aid for Scientific Research on Priority Areas (C).

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  1. Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo, 158-8501, Japan

    Hiroyuki Mizuguchi & Takao Hayakawa

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  1. Hiroyuki Mizuguchi
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  2. Takao Hayakawa
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Correspondence to Hiroyuki Mizuguchi.

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Mizuguchi, H., Hayakawa, T. Enhanced antitumor effect and reduced vector dissemination with fiber-modified adenovirus vectors expressing herpes simplex virus thymidine kinase. Cancer Gene Ther 9, 236–242 (2002). https://doi.org/10.1038/sj.cgt.7700440

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