Recombinant adenovirus expressing wild-type p53 is antiangiogenic:: A proposed mechanism for bystander effect

被引:0
作者
Nishizaki, M
Fujiwara, T
Tanida, T
Hizuta, A
Nishimori, H
Tokino, T
Nakamura, Y
Bouvet, M
Roth, JA
Tanaka, N
机构
[1] Okayama Univ, Sch Med, Dept Surg 1, Okayama 7008558, Japan
[2] Okayama Univ, Sch Med, Sect Mol Oncol, Okayama 7008558, Japan
[3] Univ Tokyo, Inst Med Sci, Mol Med Lab, Tokyo 1088639, Japan
[4] Univ Texas, MD Anderson Canc Ctr, Dept Cardiovasc & Thorac Surg, Houston, TX 77030 USA
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中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Angiogenesis is required for the growth and progression of malignancies, Recent studies have demonstrated that genetic alterations may accompany acquisition of the angiogenic phenotype, The tumor suppressor gene p53 is most frequently mutated in human cancers and is also known to be a transcriptional regulator of a variety of genes. Here, we investigated the antiangiogenic effect of the wild-type p53 (wt-p53) gene transfer on a human non-small cell lung cancer cell line. Mutant p53-expressing H226Br non-small cell lung cancer cells were transduced with the wt-p53 gene using a recombinant adenoviral vector (Ad5CMVp53) and applied to semiquantitative reverse transcription-PCRs for the detection of altered mRNA expression of angiogenic and/or antiangiogenic factors. In vivo neovascularization assay of Ad5CMVp53-infected cells was then performed using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice. We also evaluated the effect of Ad5CMVp53-infected H226Br cells on nontransduced tumor cells in vivo by s.c. inoculating mixture of cells into nu/nu mice. Ad5CMVp53 infection markedly inhibited the expression of an angiogenic factor, vascular endothelial growth factor, and increased the expression of a novel antiangiogenic factor, brain-specific angiogenesis inhibitor 1, resulting in reduced neovascularization in vivo. Mixing experiments showed that tumor cells transduced with the wt-p53 gene inhibited the in vivo tumor growth of adjacent nontransduced cells. Our data suggest that a recombinant adenovirus expressing the wt-p53 gene is antiangiogenic, which may explain, in part, the mechanism of the bystander effect induced by the wt-p53 gene transfer on adjacent tumor cells.
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页码:1015 / 1023
页数:9
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