Abstract
In this report, we investigate several examples of hypoxia-induced drug resistance and compare them with P-glycoprotein associated multidrug resistance (MDR). EMT6/Ro cells exposed to drugs in air immediately after hypoxic treatment developed resistance to adriamycin, 5-fluorouracil, and actinomycin D. However, these cells did not develop resistance to colchicine, vincristine or cisplatin. When the cells were returned to a normal oxygen environment, they lost resistance. There was no correlation between the content of adriamycin and the development of adriamycin resistance induced by hypoxia. There was no difference between the efflux of adriamycin from aerobic cells and that from hypoxia-treated cells. The mRNA for P-glycoprotein was not detected in the hypoxia-treated cells. These results suggest that hypoxia-induced drug resistance is different from P-glycoprotein associated multidrug resistance.
Highlights
EMT6/Ro cells exposed to drugs in 95% air plus 5% CO2 immediately after 12h of hypoxia developed resistance to ADR, 5-FU, and actinomycin D (ACTD)
Cells exposed to hypoxia did not develop resistance to colchicine, vincristine or cisplatin (Figure 2)
The results for hypoxia-induced drug resistance are different from those expected for classical multidrug resistance
Summary
EMT6/Ro mammary tumour cells were maintained as exponentially growing monolayers in Basal Essential Eagle's growth media (Gibco) supplemented with 10% foetal bovine serum in humidified 5% C02/95% air, as described by Heacock and Sutherland (1986). All experiments were performed on monolayers prepared 24 h in advance by seeding 5 x 105 cells onto 60 mm glass petri dishes. Cells were 60 to 70% confluent at the time of the experiments. Before being gassed with N2, the cells were supplied with 5 ml of fresh complete medium and allowed to equilibrate in a humidified 37°C incubator. Cells undergoing hypoxic stress were isolated in specially designed hypoxic chambers at room temperature (Sutherland et al, 1982). The sealed chambers were removed to a warm room (37'C) at a time point, t, referred to hereafter as '0' hours of hypoxia
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