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

Ikuo Takahashi, Yoshihiko Maehara, Hiroki Kusumoto, Shunji Kohnoe, Keizo Sugimachi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

cis-1,1-Cyclobutanedicarboxylato(2R)-2-methyl-1,4-butanediammineplatinum(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° and 43°C using EMT6/KU cells in vitro. The cytotoxicity of CDDP was enhanced at 43°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°C for 2 h simultaneously, the intracellular platinum concentration increased to 0.095±0.007 μg/107 cells (a 1.9-fold increase) for CDDP, to 0.198±0.012 μg/107 cells (a 1.3-fold increase) for NK121, and to 0.090±0.014 μg/107 cells (a 1.3-fold increase) for 254-S; respectively, as compared with the level measured after drug exposure at 37°C (P<0.05 for all drugs). The elevation in platinum concentration may be one of mechanism related to a synegistic effect of the two treatment modalities. The concomitant use of CDDP analogues and heat shows potential for possible clinical application.

Original languageEnglish
Pages (from-to)31-35
Number of pages5
JournalCancer chemotherapy and pharmacology
Volume33
Issue number1
DOIs
Publication statusPublished - Jan 1 1993

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Cyclobutanes
Cytotoxicity
Cisplatin
Hot Temperature
Platinum
Pharmaceutical Preparations
nedaplatin
In Vitro Techniques
Atomic Spectrophotometry
Spectrophotometry
Japan
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

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. / Takahashi, Ikuo; Maehara, Yoshihiko; Kusumoto, Hiroki; Kohnoe, Shunji; Sugimachi, Keizo.

In: Cancer chemotherapy and pharmacology, Vol. 33, No. 1, 01.01.1993, p. 31-35.

Research output: Contribution to journalArticle

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abstract = "cis-1,1-Cyclobutanedicarboxylato(2R)-2-methyl-1,4-butanediammineplatinum(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° and 43°C using EMT6/KU cells in vitro. The cytotoxicity of CDDP was enhanced at 43°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°C for 2 h simultaneously, the intracellular platinum concentration increased to 0.095±0.007 μg/107 cells (a 1.9-fold increase) for CDDP, to 0.198±0.012 μg/107 cells (a 1.3-fold increase) for NK121, and to 0.090±0.014 μg/107 cells (a 1.3-fold increase) for 254-S; respectively, as compared with the level measured after drug exposure at 37°C (P<0.05 for all drugs). The elevation in platinum concentration may be one of mechanism related to a synegistic effect of the two treatment modalities. The concomitant use of CDDP analogues and heat shows potential for possible clinical application.",
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