Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18237783
DOI
10.1016/j.jinorgbio.2007.12.015
PII: S0162-0134(07)00360-1
Knihovny.cz E-resources
- MeSH
- DNA Adducts chemistry MeSH
- Amantadine analogs & derivatives chemistry metabolism pharmacology MeSH
- Circular Dichroism MeSH
- DNA chemistry MeSH
- Hypoxanthine Phosphoribosyltransferase drug effects genetics MeSH
- Humans MeSH
- Mutagens chemistry metabolism pharmacology MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds chemistry metabolism pharmacology MeSH
- Antineoplastic Agents chemistry metabolism pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Amantadine MeSH
- DNA MeSH
- Hypoxanthine Phosphoribosyltransferase MeSH
- Mutagens MeSH
- Organoplatinum Compounds MeSH
- Antineoplastic Agents MeSH
Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.
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