Anticancer activity of methyl-substituted oxaliplatin analogs

Ute Jungwirth, Dimitris N Xanthos, Johannes Gojo, Anna K Bytzek, Wilfried Körner, Petra Heffeter, Sergey A Abramkin, Michael A Jakupec, Christian G Hartinger, Ursula Windberger, Markus Galanski, Bernhard K Keppler, Walter Berger

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Oxaliplatin is successfully used in systemic cancer therapy. However, resistance development and severe adverse effects are limiting factors for curative cancer treatment with oxaliplatin. The purpose of this study was to comparatively investigate in vitro and in vivo anticancer properties as well as the adverse effects of two methyl-substituted enantiomerically pure oxaliplatin analogs [[(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine] oxalatoplatinum(II) (KP1537), and [(1R,2R,4S)-4-methyl-1,2-cyclohexanediamine]oxalatoplatinum(II) (KP1691)] and to evaluate the impact of stereoisomerism. Although the novel oxaliplatin analogs demonstrated in multiple aspects activities comparable with those of the parental compound, several key differences were discovered. The analogs were characterized by reduced vulnerability to resistance mechanisms such as p53 mutations, reduced dependence on immunogenic cell death induction, and distinctly attenuated adverse effects including weight loss and cold hyperalgesia. Stereoisomerism of the substituted methyl group had a complex and in some aspects even contradictory impact on drug accumulation and anticancer activity both in vitro and in vivo. To summarize, methyl-substituted oxaliplatin analogs harbor improved therapeutic characteristics including significantly reduced adverse effects. Hence, they might be promising metal-based anticancer drug candidates for further (pre)clinical evaluation.

Original languageEnglish
Pages (from-to)719-28
Number of pages10
JournalMolecular Pharmacology
Volume81
Issue number5
DOIs
Publication statusPublished - May 2012

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Cell Cycle/drug effects
  • Cell Proliferation/drug effects
  • Cell Survival/drug effects
  • DNA/metabolism
  • Female
  • HCT116 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Organoplatinum Compounds/pharmacokinetics
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53/physiology

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