Cytotoxicity and DNA damage induced by a new platinum(II) complex with pyridine and dithiocarbamate

A new platinum(II) complex containing a pyridine nucleus and a dithiocarbamate moiety as ligands ([Pt(ESDT)(Py)Cl]) was evaluated for in vitro cytotoxicity in the cisplatin-sensitive human ovarian 2008 and in the isogenic-resistant C13* cell lines. In both cell types, a tumor cell growth inhibition...

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Bibliographic Details
Published in:Chemico-biological interactions 2002-08, Vol.140 (3), p.215-229
Main Authors: Marzano, Cristina, Fregona, Dolores, Baccichetti, Francarosa, Trevisan, Andrea, Giovagnini, Lorena, Bordin, Franco
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Cattle
Cisplatin - analogs & derivatives
Cisplatin - pharmacokinetics
Cisplatin - pharmacology
Cytotoxicity
DNA - drug effects
DNA - metabolism
DNA Adducts - metabolism
DNA binding
DNA Damage
Female
Humans
Organoplatinum Compounds - pharmacokinetics
Organoplatinum Compounds - pharmacology
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - metabolism
Plasmids - metabolism
Platinum(II) complex
Pyridines - pharmacokinetics
Pyridines - pharmacology
Thiocarbamates - pharmacokinetics
Thiocarbamates - pharmacology
Tumor Cells, Cultured
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Summary:A new platinum(II) complex containing a pyridine nucleus and a dithiocarbamate moiety as ligands ([Pt(ESDT)(Py)Cl]) was evaluated for in vitro cytotoxicity in the cisplatin-sensitive human ovarian 2008 and in the isogenic-resistant C13* cell lines. In both cell types, a tumor cell growth inhibition greater than cisplatin and a complete lack of cross-resistance in C13* cells were found. Despite its molecular size, [Pt(ESDT)(Py)Cl] accumulation was much higher than cisplatin both in parent and resistant cells. Studying the mechanism of action in cell-free media, we established that [Pt(ESDT)(Py)Cl] more efficiently interacts with DNA in vitro compared to cisplatin maintaining a binding preference for GG rich sequences of DNA. On the contrary, DNA platination in vivo by [Pt(ESDT)(Py)Cl] was found lower than cisplatin. An analysis of the type of DNA lesions induced by [Pt(ESDT)(Py)Cl] suggests that the cytotoxic efficacy and the ability to overcome cisplatin resistance seem to be related to a different mechanism of interaction with DNA and/or with other key cellular components.
ISSN:0009-2797
1872-7786
DOI:10.1016/S0009-2797(02)00037-6