Effect of hypoxia and acidosis on the cytotoxicity of mitoxantrone, bisantrene and amsacrine and their platinum complexes at normal and hyperthermic temperatures

In an effort to synthesize drugs which would become much more cytotoxic at clinically achievable hyperthermic temperatures, complexes of the tetrachloro-platinum(II) dianion were made with two anthracene dye derivatives. MITOX and BISANT, and the acridine dye derivative m-AMSA. As compared with the parent drug. PtCl₄(MITOX)₂ was less cytotoxic at 37°C and more cytotoxic at 42°C and 43°C especially at pH 6.45. In contrast, the PtCl₄(BISANT)₂ was more cytotoxic than BISANT under all conditions M-AMSA was again shown to be less cytotoxic at elevated temperatures but PtCl₄(m-AMSA)₂ was more cytotoxic especially at 43°C and pH 6.45. Platinum levels in cells treated for 1 hr with 25 μM at 37°C, 42°C and at pH 7.40 versus pH 6.45 demonstrated no significant differences depending on temperature or pH except for PtCl₄(MITOX)₂ where approximately 4 times higher intracellular platinum levels were present at pH 6.45 versus pH 7.40, although this finding did not correlate with cytotoxicity. These results suggest that PtCl₄(MITOX)₂ and PtCl₄(m-AMSA)₂ may be highly interactive drugs with local hyperthermia.