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Revisiting [PtCl₂(cis-1,4-DACH)]: an underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer.

Abstract
Although the encouraging antitumor activity of [PtCl(2)(cis-1,4-DACH)] (1; DACH = diaminocyclohexane) was shown in early studies almost 20 years ago, the compound has remained nearly neglected. In contrast, oxaliplatin, containing the isomeric 1(R),2(R)-DACH carrier ligand, enjoys worldwide clinic application as a most important therapeutic agent in the treatment of colorectal cancer. By extending the investigation to human chemotherapy-resistant cancer cells, we have demonstrated the real effectiveness of 1 in circumventing cisplatin and oxaliplatin resistance in LoVo colon cancer cells. The uptake of compound 1 by the latter cells was similar to that of sensitive LoVo cells. This is not the case for all other compounds considered in this investigation. Interaction with double-stranded DNA, investigated by a biosensor assay and by quantum mechanical/molecular mechanical geometry optimization of the 1,2-GG intrastrand cross-link, does not show significant differences between 1 and oxaliplatin. However, the DNA adducts of 1 are removed from repair systems with lower efficiency and are more effective in inhibiting DNA and RNA polymerase.
AuthorsNicola Margiotta, Cristina Marzano, Valentina Gandin, Domenico Osella, Mauro Ravera, Elisabetta Gabano, James A Platts, Emanuele Petruzzella, James D Hoeschele, Giovanni Natile
JournalJournal of medicinal chemistry (J Med Chem) Vol. 55 Issue 16 Pg. 7182-92 (Aug 23 2012) ISSN: 1520-4804 [Electronic] United States
PMID22788918 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • DNA Adducts
  • Nucleic Acid Synthesis Inhibitors
  • Organoplatinum Compounds
  • oxaliplatin
  • DNA
  • DNA-Directed DNA Polymerase
  • Cisplatin
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
  • Biosensing Techniques
  • Carcinoma, Lewis Lung (drug therapy)
  • Cell Line, Tumor (drug effects)
  • Cisplatin (pharmacology)
  • Colorectal Neoplasms (drug therapy)
  • DNA (chemistry)
  • DNA Adducts (chemistry)
  • DNA-Directed DNA Polymerase (chemistry)
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Nucleic Acid Synthesis Inhibitors
  • Organoplatinum Compounds (chemistry, pharmacology, therapeutic use)
  • Quantum Theory

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