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 degrees C and more cytotoxic at 42 degrees C and 43 degrees 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 degrees C and pH 6.45. Platinum levels in cells treated for 1 hr with 25 microM at 37 degrees C, 42 degrees 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.
Herman
T S
TS
Dana-Farber Cancer Institute, Boston, MA 02115.
Teicher
B A
BA
Varshney
A
A
Khandekar
V
V
Brann
T
T
D000138:Acidosis; D000677:Amsacrine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*
D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D009944:Organoplatinum Compounds; C075423:amsacrine-tetrachloroplatinum dianion complex; C075424:bisantrene-tetrachloroplatinum dianion complex; C075422:mitoxantrone-tetrachloroplatinum dianion complex; D000677:Amsacrine; C031404:bisantrene; D008942:Mitoxantrone