Unique action determinants of double acting topoisomerase inhibitor, TAS-103.
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.
Okamoto
R
R
Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Takano
H
H
Sekikawa
T
T
Tanaka
T
T
Toyada
M
M
Ukon
K
K
Tanimoto
K
K
Kumazaki
T
T
Nishiyama
M
M
D000634:Aminoquinolines / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005656:Fungal Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D000077146:Irinotecan; D024101:Mitochondrial Proteins; D012333:RNA, Messenger / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000634:Aminoquinolines; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D007192:Indenes; C082883:MGM1 protein, S cerevisiae; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D019328:Buthionine Sulfoximine; D005047:Etoposide; D000077146:Irinotecan; D019204:GTP-Binding Proteins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D002166:Camptothecin; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one