Highly augmented cytopathic effect of a fiber-mutant E1B-defective adenovirus for gene therapy of gliomas.
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 AdvE1AdB-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.
Shinoura
N
N
Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Yoshida
Y
Y
Tsunoda
R
R
Ohashi
M
M
Zhang
W
W
Asai
A
A
Kirino
T
T
Hamada
H
H
D017501:Adenovirus E1B Proteins / Q000172:deficiency* / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002213:Capsid / Q000172:deficiency* / Q000235:genetics; D036022:Capsid Proteins; D003588:Cytopathogenic Effect, Viral; D003673:Defective Viruses / Q000235:genetics / Q000502:physiology*; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007763:Lac Operon; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus