title: Effect of hypoxia and acidosis on the cytotoxicity of mitoxantrone, bisantrene and amsacrine and their platinum complexes at normal and hyperthermic temperatures.
abstract: 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.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: T S
authors.initials: TS
authors.lastname: Herman
authors.forename: B A
authors.initials: BA
authors.lastname: Teicher
authors.forename: A
authors.initials: A
authors.lastname: Varshney
authors.forename: V
authors.initials: V
authors.lastname: Khandekar
authors.forename: T
authors.initials: T
authors.lastname: Brann
mesh_terms: 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*
chemical_list: 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