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First published on August 8, 2006; DOI: 10.1124/mol.106.027730

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Received for publication June 7, 2006.
Revised August 2, 2006.
Accepted for publication August 8, 2006.

Molecular aspects of antitumor effects of a new platinum(IV) drug

Jana Kasparkova 1, Olga Novakova 1, Oldrich Vrana 1, Francesco Intini 2, Giovanni Natile 2, Viktor Brabec 1*

1 Institute of Biophysics AS CR, Brno 2 University of Bari

* Address correspondence to: E-mail: brabec{at}ibp.cz

Abstract

The new platinum(IV) complex cis,trans,cis-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [adamplatin(IV)] appears 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 "classical" 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).


Key words: DNA binding sites, Structure-activity relationships and modeling, DNA damage and repair, Glutathione, Mechanisms of cell killing/apoptosis, Pharmacokinetics, metabolism and activation


eLetters:

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Method of preparation and identity of compounds tested
Frantisek Zak
MolPharm Online, 9 Jan 2007 [Full text]
Author Response to Zak letter
Viktor Brabec
MolPharm Online, 9 Jan 2007 [Full text]

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