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- Title
Cytotoxicity of replication-competent adenoviruses powered by an exogenous regulatory region is not linearly correlated with the viral infectivity/gene expression or with the E1A-activating ability but is associated with the p53 genotypes.
- Authors
Suguru Yamauchi; Boya Zhong; Kiyoko Kawamura; Shan Yang; Shuji Kubo; Masato Shingyoji; Ikuo Sekine; Yuji Tada; Koichiro Tatsumi; Hideaki Shimada; Kenzo Hiroshima; Masatoshi Tagawa; Yamauchi, Suguru; Zhong, Boya; Kawamura, Kiyoko; Yang, Shan; Kubo, Shuji; Shingyoji, Masato; Sekine, Ikuo; Tada, Yuji
- Abstract
<bold>Background: </bold>Replication-competent adenoviruses (Ad) produced cytotoxic effects on infected tumors and have been examined for the clinical applicability. A biomarkers to predict the cytotoxicity is valuable in a clinical setting.<bold>Methods: </bold>We constructed type 5 Ad (Ad5) of which the expression of E1A gene was activated by a 5' regulatory sequences of survivin, midkine or cyclooxygenase-2, which were highly expressed in human tumors. We also produced the same replication-competent Ad of which the fiber-knob region was replaced by that of Ad35 (AdF35). The cytotoxicity was examined by a colorimetric assay with human tumor cell lines, 4 kinds of pancreatic, 9 esophageal carcinoma and 5 mesothelioma. Ad infectivity and Ad-mediated gene expression were examined with replication-incompetent Ad5 and AdF35 which expressed the green fluorescence protein gene. Expression of cellular receptors for Ad5 and AdF35 was also examined with flow cytometry. A transcriptional activity of the regulatory sequences was investigated with a luciferase assay in the tumor cells. We then investigated a possible correlation between Ad-mediated cytotoxicity and the infectivity/gene expression, the transcriptional activity or the p53 genotype.<bold>Results: </bold>We found that the cytotoxicity was greater with AdF35 than with Ad5 vectors, but was not correlated with the Ad infectivity/gene expression irrespective of the fiber-knob region or the E1A-activating transcriptional activity. In contrast, replication-competent Ad produced greater cytotoxicity in p53 mutated than in wild-type esophageal carcinoma cells, suggesting a possible association between the cytotoxicity and the p53 genotype.<bold>Conclusions: </bold>Sensitivity to Ad-mediated cytotoxic activity was linked with the p53 genotype but was not lineally correlated with the infectivity/gene expression or the E1A expression.
- Subjects
ADENOVIRUSES; CELL-mediated cytotoxicity; TUMOR growth; TUMOR treatment; GENETIC regulation
- Publication
BMC Cancer, 2017, Vol 17, p1
- ISSN
1471-2407
- Publication type
journal article
- DOI
10.1186/s12885-017-3621-x