Enhancing effect of pre-treatment of cells with misonidazole in hypoxia on their response to melphalan in air.

Pre-treatment of hypoxic cells with misonidazole (MISO) can render these cells more sensitive to a subsequent treatment with melphalan. Results in this paper show that this enhancement (or chemopotentiation) depends on the contact time and concentration of MISO, on the melphalan concentration and also on the cultural history of the cells. Damage due to hypoxic pre-incubation in MISO can be repaired if cells are subsequently aerated at 37 degrees C. In contrast, for cells washed free of MISO and then held under N2 at 37 degrees C, repair is much slower. No repair occurs when cells are held in air at 0 degrees C. The kinetics and extent of repair were dependent on the cells prior culture. Thus for exponential cells repair was complete after approximately 4 h, whereas for plateau-phase cells and cells with prior chronic hypoxia, repair was only partially complete after this time. Dithiothreitol was shown to protect partially against the enhancement of melphalan toxicity. Increased cell killing is also obtained if cells are given high concentrations of MISO (50 mM) in air during exposure to melphalan.