Molecular aspects of antitumor effects of a new platinum(IV) drug
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
16896071
DOI
10.1124/mol.106.027730
PII: S0026-895X(24)04224-X
Knihovny.cz E-resources
- MeSH
- Adamantane analogs & derivatives therapeutic use MeSH
- DNA Adducts drug effects MeSH
- Cell-Free System MeSH
- DNA-Directed RNA Polymerases metabolism MeSH
- DNA biosynthesis MeSH
- HeLa Cells MeSH
- HIV-1 enzymology MeSH
- Rats MeSH
- Ascorbic Acid metabolism MeSH
- Humans MeSH
- Molecular Sequence Data MeSH
- Cell Line, Tumor MeSH
- Neoplasms drug therapy MeSH
- DNA Repair genetics MeSH
- Organoplatinum Compounds therapeutic use MeSH
- Platinum metabolism MeSH
- Plasmids genetics MeSH
- High Mobility Group Proteins metabolism MeSH
- Antineoplastic Agents therapeutic use MeSH
- Cross-Linking Reagents MeSH
- RNA-Directed DNA Polymerase metabolism MeSH
- Base Sequence MeSH
- Sulfur Compounds metabolism MeSH
- Viral Proteins metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- (PtCl(2)(CH(3)COO)(2)-(NH(3))(1-adamantylamine)) MeSH Browser
- Adamantane MeSH
- DNA Adducts MeSH
- bacteriophage T7 RNA polymerase MeSH Browser
- DNA-Directed RNA Polymerases MeSH
- DNA MeSH
- Ascorbic Acid MeSH
- Organoplatinum Compounds MeSH
- Platinum MeSH
- High Mobility Group Proteins MeSH
- Antineoplastic Agents MeSH
- Cross-Linking Reagents MeSH
- RNA-Directed DNA Polymerase MeSH
- Sulfur Compounds MeSH
- Viral Proteins MeSH
The new platinum(IV) complex cis,trans,cis-[PtCl(2)(CH(3)COO)(2)-(NH(3))(1-adamantylamine)] [adamplatin(IV)] seems promising for the perspective application in therapy of corresponding tumors. It is therefore of great interest to understand details of mechanisms underlying its biological efficacy. Cellular uptake of the drug, alterations in the target DNA induced by platinum drugs along with processing of platinum-induced damage to DNA and drug inactivation by sulfur-containing compounds belong to major pharmacological factors affecting antitumor effects of platinum compounds. We examined in the present work the significance of these factors in the mechanism of antitumor effects of adamplatin(IV) and compared the results with those of the parallel studies performed with "conventional" cisplatin. The results show that deactivation of adamplatin(IV) by sulfur-containing compounds (such as glutathione or metallothioneins) is likely to play a less significant role in the mechanism of resistance of tumor cells to adamplatin(IV) in contrast to the role of these reactions in the effects of cisplatin. Moreover, the treatment of tumor cells with adamplatin(IV) does not result in DNA modifications that would be markedly different from those produced by cisplatin. In contrast, the effects of other factors, such as enhanced accumulation of the drug in cells, strong inhibition of DNA polymerization by these adducts, lowered DNA repair, and DNA-protein cross-linking are different from the effects of these factors in the mechanism underlying activity of cisplatin. Hence, the differences between effects of adamplatin(IV) and cisplatin observed in the present work on molecular level may help understand the unique activity of adamplatin(IV).
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