Abstract
ONYX-015 has been reported to kill selectively tumor cells lacking functional p53. Genetic alterations of INK4a/ARF locus, which is a predominant event in malignant pleural mesothelioma, may result in loss of p14(ARF) and subsequent disruption of p53 pathway in cancer cells. In the present study, ONYX-015 was able to kill three mesothelioma cell lines (H28, H513, and 211H) with wild-type p53 but lacking p14(ARF). In contrast, MS-1 mesothelioma cells, which expressed both p53 and p14(ARF), were resistant to ONYX-015. Introducing p14(ARF) gene into the H28 cell, a mesothelioma cell without p14(ARF) expression, significantly increased the resistance of this cell line to the cytolytic effect of ONYX-015. Our results suggest that human mesotheliomas with wild-type p53 yet lacking p14(ARF) are potential candidates for ONYX-015 therapy.
MeSH terms
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Adenovirus E1B Proteins / genetics
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Adenoviruses, Human / genetics
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Adenoviruses, Human / physiology*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Cyclins / genetics
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Cytopathogenic Effect, Viral / genetics
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Genes, p53
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Genetic Therapy / methods*
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Genetic Vectors / genetics
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Humans
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Mesothelioma / genetics
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Mesothelioma / metabolism
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Mesothelioma / therapy*
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Mesothelioma / virology
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Pleural Neoplasms / genetics
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Pleural Neoplasms / metabolism
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Pleural Neoplasms / therapy*
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Pleural Neoplasms / virology
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Protein Biosynthesis
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Proteins / genetics
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Proteins / physiology*
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Tumor Cells, Cultured
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / physiology*
Substances
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Adenovirus E1B Proteins
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Proteins
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53