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[Cancer Research 59, 3411-3416, July 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 3411-3416, July 15, 1999]
© 1999 American Association for Cancer Research

Experimental Therapeutics

Highly Augmented Cytopathic Effect of a Fiber-mutant E1B-defective Adenovirus for Gene Therapy of Gliomas1

Nobusada Shinoura, Yoko Yoshida, Rikiya Tsunoda, Makoto Ohashi, Weiping Zhang, Akio Asai, Takaaki Kirino and Hirofumi Hamada2

Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455 [N. S., Y. Y., M. O., W-p. Z., H. H.]; Department of Neurosurgery, Tokyo University, Tokyo 113 [N. S., A. A., T. K.]; Department of Anatomy and Histology, Fukushima Medical College, Fukushima 960-1295 [R. T.]; and CREST (Core Research for Evolutional Science and Technology), Kawaguchi 332-0012 [T. K.], Japan

An E1B 55-kDa gene-defective adenovirus (Adv), ONYX-015, has been reported to be a highly useful replication-competent Adv that shows cytopathic effect for cancers with an abnormal p53 gene, without damaging normal tissues. In this study, we combined this Adv (Adv-E1AdB) with a fiber mutation, F/K20, which has a stretch of 20 lysine residues added at the COOH-terminus of the fiber and shows high transduction efficiency to gliomas. In U-373 MG glioma cells, the transduction efficiency of Adv-F/K20 for lacZ was nine times higher than that of the Adv with wild-type fiber (Adv-F/wt) for lacZ. At a multiplicity of infection of 30, the replication efficiency of Adv-E1AdB-F/K20 was 11 times higher than that of Adv-E1AdB with wt fiber (Adv-E1AdB-F/wt). The ED50 value of Adv-E1AdB-F/K20 to U-373 MG cells, which is a measure of the in vitro cytopathic effect, was 32 times greater than that of Adv-E1AdB-F/wt. Injection of Adv-E1AdB-F/K20 suppressed the in vivo growth of tumors. The antitumoral effect of Adv-E1AdB-F/K20 was remarkably stronger than that of Adv-E1AdB-F/wt. A greater quantity of replicated virus protein (hexon) by infection with Adv-E1AdB-F/K20 was demonstrated in vitro and in vivo, compared with that of Adv-E1AdB-F/wt. In conclusion, gene therapy using Adv-E1AdB-F/K20, which drastically augmented the antitumoral effect of Adv-E1AdB, will be a promising therapeutic approach for gliomas.




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Copyright © 1999 by the American Association for Cancer Research.