Interaction of PtCl4(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 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.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, Massachusetts.
Herman
T S
TS
Pfeffer
M R
MR
Alvarez Sotomayor
E
E
Khandekar
V S
VS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003979:Diazonium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D005354:Fibrosarcoma; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010984:Platinum / Q000032:analysis; D013054:Spectrophotometry, Atomic; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects
D000970:Antineoplastic Agents; D003979:Diazonium Compounds; D009944:Organoplatinum Compounds; C060457:platinum(II) tetrachlorodianion (Fast Black)2; D010984:Platinum; D002945:Cisplatin