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.

• Authors: Nicola Margiotta, Cristina Marzano, Valentina Gandin, Domenico Osella, Mauro Ravera, Elisabetta Gabano, James A Platts, Emanuele Petruzzella, James D Hoeschele, Giovanni Natile
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 16 Pg. 7182-92 (Aug 23 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22788918 (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)
• Oxaliplatin
• Quantum Theory