Effect of Hypoxia and Acidosis on the Cytotoxicity of Four Platinum Complexes at Normal and Hyperthermic Temperatures¹

The cytotoxicities of cis-diamminedichloroplatinum(II) (CDDP) and of three recently developed dichloro complexes of bivalent platinum with radiosensitizing ligands [(1,2-diamino-4-nitrobenzene)dichloroplatinum(II) (Plato), trans-bis(2-amino-5-nitrothiazole)dichloroplatinum(II) (Plant), and trans-bis(2-nitroimidazole)dichloroplatinum(II) (NIPt)] were evaluated at 37°C, 42°C, and 43°C at normal pH, at pH 6.45, and under normally oxygenated and hypoxic conditions in EMT6 cells in vitro. For CDDP, marked hyperthermic sensitization to the drug was evident in normally oxygenated cells, but hypoxic cells showed essentially no sensitization to the cytotoxicity of CDDP at elevated temperature at normal pH. Low pH further increased the cytotoxicity of CDDP toward normally oxygenated but not hypoxic cells at 37°C and 42°C. At 43°C, however, low pH increased the cytotoxicity of CDDP toward both normally oxygenated and hypoxic cells, restoring nearly the full sensitizing effect of hyperthermia on CDDP cytotoxicity in the hypoxic cells. Plato was much more cytotoxic toward hypoxic than normally oxygenated cells under all culture conditions. At normal pH, hyperthermia increased the cytotoxicity of Plato in both hypoxic and normally oxygenated cells. At low pH, however, the cytotoxicity of Plato was inhibited at all temperatures and in both normally oxygenated and hypoxic cells. Plant was also more toxic to both normally oxygenated and hypoxic cells at elevated temperatures at normal pH. In contrast to Plato, however, Plant became much more cytotoxic toward hypoxic cells and showed increased cytotoxicity in normally oxygenated cells at low pH. Hyperthermia, however, did not further increase the rate of cell killing by Plant at low pH. NIPt, at the concentrations tested, was essentially nontoxic to cells at normal pH at 37°C. Hyperthermia significantly increased the killing of hypoxic cells by NIPt under both normal and low pH conditions, but little cytotoxicity was noted for NIPt in normally oxygenated cells under any culture conditions.

These results demonstrate that pH and the level of oxygenation of cells significantly affect the cytotoxicity of drugs at both normal and elevated temperatures. This sort of investigation may help delineate optimum drugs for use against environmentally determined subpopulations of cells within tumors.