期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 16, 页码 7182-7192出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3006838
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资金
- University of Bari (Fondi di Ateneo)
- Italian Ministero dell'Universita e della Ricerca (PRIN) [2009WCNS5C_004]
- European Commission (EC) (European Cooperation in Science and Technology (COST) Action) [CM1105]
- Inter-University Consortium for Research on the Chemistry of Metal Ions in Biological Systems (CIRCMSB, Bari, Italy)
- Leverhulme Trust
Although the encouraging antitumor activity of [PtCl2(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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