Abstract
O6-methylguanine-DNA methyltransferase (MGMT), gamma-glutamylcysteine synthetase (gamma-GCS), and glutathione (GSH) are found to participate in resistance to TAS-103, a topoisomerase I/II inhibitor. In 13 human cancer cell lines, MGMT expression correlated with IC50 for TAS-103, whereas gamma-GCS expression inversely correlated with the IC50 value, suggesting MGMT may work to decrease TAS-103 activity but gamma-GCS may increase it. A reduced gamma-GCS and GSH, and an increased MGMT were associated with the development of resistance in A549 and DLD cells, and gamma-GCS inhibition by buthionine sulphoximine increased the TAS-103 resistance, whereas MGMT inhibition by both O6-benzyl-guanine and MGMT-antisense transfection sensitized cells to TAS-103.
MeSH terms
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Aminoquinolines / pharmacology*
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Antineoplastic Agents, Phytogenic / pharmacology
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Blotting, Northern
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Blotting, Western
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Buthionine Sulfoximine / pharmacology
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Camptothecin / analogs & derivatives
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Camptothecin / pharmacology
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Drug Resistance
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Enzyme Inhibitors / pharmacology*
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Etoposide / pharmacology
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Fungal Proteins / metabolism
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GTP-Binding Proteins*
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Glutamate-Cysteine Ligase / metabolism
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Glutathione / metabolism
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Humans
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Indenes / pharmacology*
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Irinotecan
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Mitochondrial Proteins*
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RNA, Messenger / metabolism*
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Saccharomyces cerevisiae Proteins*
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Topoisomerase I Inhibitors*
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Topoisomerase II Inhibitors*
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Tumor Cells, Cultured / drug effects*
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Tumor Cells, Cultured / metabolism
Substances
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Aminoquinolines
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Antineoplastic Agents, Phytogenic
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Enzyme Inhibitors
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Fungal Proteins
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Indenes
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MGM1 protein, S cerevisiae
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Mitochondrial Proteins
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RNA, Messenger
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Saccharomyces cerevisiae Proteins
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Topoisomerase I Inhibitors
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Topoisomerase II Inhibitors
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Buthionine Sulfoximine
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Etoposide
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Irinotecan
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GTP-Binding Proteins
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Glutamate-Cysteine Ligase
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Glutathione
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Camptothecin
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6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one