Chemopotentiation of mitomycin C cytotoxicity in vitro by platinum complexes

Abstract

The potential of cis-diamminedichloroplatinum(II) (CDDP), trans-di(2-nitroimidazole)dichloro-platinum(II) (NIPt), trans-di(2-amino-5-nitrothiazole)dichloroplatinum(II) (Plant), cis-(1,2-diamino-4-nitrobenzene)dichloroplatinum(II) (Plato), and cis-di-pyridinedichloroplatinum(II) (PyPt) to act as chemosensitizers of mitomycin C cytotoxicity toward EMT6 cells under oxygenated and hypoxic conditions has been assessed. Cells were given a 1 h treatment with the platinum complex under oxygenated or hypoxic conditions and then an additional one hour of exposure to the combination. Two concentrations of each platinum complex, 0.1 and 0.01 microM, were tested in combination with mitomycin C at 1, 0.1 and 0.01 microM. The results were analyzed via isobolograms. Under oxygenated conditions the combinations of the various platinum complexes and mitomycin C produced approximately a 2-3-fold enhancement in cell killing. Under hypoxic conditions enhancements of 5-fold, 20-fold and 60-fold were obtained with CDDP and 1, 0.1 and 0.01 microM mitomycin C, respectively. The combinations of 0.1 microM NIPT and mitomycin C under hypoxic conditions were 30-60-fold more cytotoxic than expected by additivity. With 0.01 microM NIPT a 15-23-fold enhancement of mitomycin C cytotoxicity was observed. The Plant-mitomycin C combinations produced a 5-14-fold enhancement in cell killing under hypoxic conditions. Under hypoxic conditions the combinations of 0.1 microM Plato and mitomycin C were 30-60-fold more cytotoxic than expected. At 0.01 microM Plato an 8-16-fold enhancement in cytotoxicity was observed under hypoxic conditions. PyPt and mitomycin C produced an 8-16-fold enhancement in cytotoxicity under hypoxic conditions. Overall, the platinum complexes containing radiosensitizing nitroaromatic groups were no more active in producing enhanced effects than cis-diamminedichloroplatinum(II).