RESUMO
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.
