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.
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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)
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Chemical References |
- Antineoplastic Agents
- DNA Adducts
- Nucleic Acid Synthesis Inhibitors
- Organoplatinum Compounds
- Oxaliplatin
- DNA
- DNA-Directed DNA Polymerase
- Cisplatin
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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
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