title: Heat enhances the cytotoxicity of cis-diamminedichloroplatinum(II) and its analogues cis-1,1-cyclobutane-dicarboxylato(2R)-2-methyl-1,4- butanediammineplatinum(II) and cis-diammine(glycolato)platinum in vitro.
abstract: cis-1,1-Cyclobutanedicarboxylato(2R)-2-methyl-1,4-butanediammin eplatinum(II) (NK121) and cis-diammine(glycolato)platinum (254-S), analogues of cis-diamminedichloroplatinum (II) (CDDP) with reduced nephrotoxicity, are under clinical phase trial in Japan. Since CDDP has been shown to be more cytotoxic under conditions of an elevated temperature, we tested the cytotoxicity and cellular uptake of these analogues at 37 degrees and 43 degrees C using EMT6/KU cells in vitro. The cytotoxicity of CDDP was enhanced at 43 degrees C, and that of NK121 and 254-S was also enhanced, in a dose- and time-dependent manner. The 90% cytotoxic concentration (IC90) of each drug was reduced 2.9-fold for CDDP, 2.5-fold for NK121, and 2.2-fold for 254-S. Cytotoxicity was maximal when the two modalities were used simultaneously for all three drugs. The intracellular platinum concentration was assayed using flameless atomic absorption spectrophotometry. When exposed to IC90 drug concentration at 43 degrees C for 2 h simultaneously, the intracellular platinum concentration increased to 0.095 +/- 0.007 micrograms/10(7) cells (a 1.9-fold increase) for CDDP, to 0.198 +/- 0.012 micrograms/10(7) cells (a 1.3-fold increase) for NK121, and to 0.090 +/- 0.014 micrograms/10(7) cells (a 1.3-fold increase) for 254-S; respectively, as compared with the level measured after drug exposure at 37 degrees C (P < 0.05 for all drugs). The elevation in platinum concentration may be one of mechanism related to a synergistic effect of the two treatment modalities. The concomitant use of CDDP analogues and heat shows potential for possible clinical application.
authors.affiliation: Cancer Center of Kyushu University Hospital, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Maehara
authors.forename: H
authors.initials: H
authors.lastname: Kusumoto
authors.forename: S
authors.initials: S
authors.lastname: Kohnoe
authors.forename: K
authors.initials: K
authors.lastname: Sugimachi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006358:Hot Temperature; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C055425:NK 121; C053989:nedaplatin; D016190:Carboplatin; D002945:Cisplatin