Interaction of PtCLi(Fast Black)2 with Hyperthermia

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 PtCl2(Fast Blacky is a tight ion pair. In experimentally growing EMT6 cells in vitro, PtC4(Fast Black)2 killed cells in a log-linear manner which increased as the temperature of the exposures was increased from 37 to 42°C or 43°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 µM cisplatin or PtCl4(Fast Blacky demonstrated that platinum levels were between 170- and 200-fold higher after exposure to PtCl4(Fast Blacky. In vivo studies in the FSallC murine fibrosarcoma showed, again, that PtCl4(Fast Blacky killed in a log-linear manner. Treatment of tumors placed in the thigh with 43°C., 30-min hyperthermia immediately following i.p. injection of PtCU(Fast Black)2 was dose modifying. One hundred mg/kg of PtCUFast Blacky produced a 4.6-day tumor growth delay which increased to 6.4 days with 43°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. PtCL,(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.