Unique action determinants of double acting topoisomerase inhibitor, TAS-103
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- Published online on: November 1, 2001 https://doi.org/10.3892/ijo.19.5.921
- Pages: 921-927
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Abstract
O6-methylguanine-DNA methyltransferase (MGMT), γ-glutamylcysteine synthetase (γ-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 γ-GCS expression inversely correlated with the IC50 value, suggesting MGMT may work to decrease TAS-103 activity but γ-GCS may increase it. A reduced γ-GCS and GSH, and an increased MGMT were associated with the development of resistance in A549 and DLD cells, and γ-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.
