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Int J Oncol ; 19(5): 921-7, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11604989

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.


Subject(s)
Aminoquinolines/pharmacology , Enzyme Inhibitors/pharmacology , GTP-Binding Proteins , Indenes/pharmacology , Mitochondrial Proteins , RNA, Messenger/metabolism , Saccharomyces cerevisiae Proteins , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Tumor Cells, Cultured/drug effects , Antineoplastic Agents, Phytogenic/pharmacology , Blotting, Northern , Blotting, Western , Buthionine Sulfoximine/pharmacology , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Drug Resistance , Etoposide/pharmacology , Fungal Proteins/metabolism , Glutamate-Cysteine Ligase/metabolism , Glutathione/metabolism , Humans , Irinotecan , Tumor Cells, Cultured/metabolism
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