Hypoxia is often observed in solid
tumors. The aim of this study was to investigate the efficacy of seven cytotoxic drugs against the pulmonary
adenocarcinoma multidrug-resistant cell line A549/MDR under
hypoxia (3% O(2)), and to explore the possible mechanisms for the change of efficacy. The efficacy of cytotoxic drugs under hypoxic conditions was different from that under normoxia. Proliferation of A549/MDR cells was enhanced under
hypoxia and no close correlation was found between proliferation and cytotoxic effects. Under
hypoxia, the efficacy of rhodamine123 efflux was unchanged; the culture medium became more acidic and the generation of
reactive oxygen species (ROS) was decreased. The intracellular fluorescence intensity of
daunorubicin was much lower in this acidic microenvironment. These results indicate that susceptibility to drugs was greatly influenced by
hypoxia and different intracellular
drug concentrations induced by microenvironment acidification which may be the main cause of the change in
drug efficacy. In addition, proliferation may change resistance to study drugs under
hypoxia for A549/MDR cells. The decreased generation of ROS may be another reason for the resistance of A549/MDR cell line to
daunorubicin under hypoxic conditions.
Drug exclusion mediated by P-gp may not be the key reason.