We are developing complexes of negatively charged
PtCl4 with positively charged nuclear
dyes as new
antitumor agents for use alone and in conjunction with
hyperthermia and/or radiation. Elemental analysis has shown that the complex
PtCl4(Fast Black)2 is a tight ion pair. In experimentally growing EMT6 cells in vitro,
PtCl4(Fast Black)2 killed cells in a log-linear manner which increased as the temperature of the exposures was increased from 37 to 42 degrees C or 43 degrees C. In addition, cell kill was also increased under conditions of low pH (6.45), especially in hypoxic cells treated at elevated temperature. Measurement of intracellular
platinum levels after exposure to 25 microM
cisplatin or
PtCl4(Fast Black)2 demonstrated that
platinum levels were between 170- and 200-fold higher after exposure to
PtCl4(Fast Black)2. In vivo studies in the FSaIIC murine
fibrosarcoma showed, again, that
PtCl4(Fast Black)2 killed in a log-linear manner. Treatment of
tumors placed in the thigh with 43 degrees C, 30-min
hyperthermia immediately following i.p. injection of
PtCl4(Fast Black)2 was dose modifying. One hundred mg/kg of
PtCl4(Fast Black)2 produced a 4.6-day
tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min
hyperthermia immediately following i.p. injection of
PtCl4(Fast Black)2 was does modifying. One hundred mg/kg of
PtCl4(Fast Black)2 produced a 4.6-day
tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min
hyperthermia (growth delay for
hyperthermia alone was 1.4 days), and 500 mg/kg produced a 5.6-day delay which increased to 11.0 days with
hyperthermia. In contrast,
cisplatin (5 mg/kg) produced a 4.4-day delay which increased to 5.9 days with
hyperthermia.
PtCl4(Fast Black)2 was well tolerated by animals, and the maximally tolerated dose was approximately 650 mg/kg. This new complex appears quite active as an
antitumor agent alone and in conjunction with
hyperthermia, and, since other studies have shown it to interact positively with radiation, this agent seems a very appropriate candidate for further development as a clinical anticancer
drug.