Drug resistance in Chinese hamster ovary cells during recovery from severe hypoxia

Chinese hamster ovary cells exposed to hypoxia developed an 80-fold resistance to a subsequent 1-hour exposure to doxorubicin (ADR) in air. Recovery in air before drug exposure resulted in loss of resistance. Cells exposed to hypoxia for 20 hours followed by a 15-hour recovery were still twofold to threefold more resistant than aerobic cells to a short pulse of ADR. A subpopulation of cells was generated that was at least twice as large as aerobic cells and contained greater than normal G2-M DNA content. This subpopulation showed no resistance to a continuous exposure to either ADR or methotrexate, nor was it more resistant to a pulse of ADR than the remaining cells with normal DNA content. Our data indicate that hypoxia can produce significant ADR resistance. However, conditions resulting in overproduced DNA did not cause significant additional resistance.