Genotoxicity of novel trans-platinum(II) complex with diethyl (pyridin-4-ylmethyl)phosphate in human non-small cell lung cancer cells A549.

Abstract

The dynamic development of metal-containing anticancer drugs has started since the discovery of cis-diamminedichloroplatinum(II). For many years it was believed that trans platinum(II) compounds were non-active as antitumour agents because trans-diamminedichloroplatinum is biologically inactive although it binds to DNA and also forms monoadducts and cross-links. In the present work the ability of a novel platinum(II) compound trans-[PtCl(2)(4-pmOpe)(2)] to induce DNA damage in human non-small cell lung cancer cells A549 was examined using the alkaline comet assay. The obtained results revealed that the novel trans platinum(II) complex induced DNA strand breaks, which were effectively repaired during 2h of post-incubation, and cross-links which remained unrepaired under these test conditions. Apart from that, the modified comet assay with incubation with proteinase K was used to verify the ability of trans-[PtCl(2)(4-pmOpe)(2)] and cis-DDP to form DNA-protein cross-links. It has been proved that only trans-[PtCl(2)(4-pmOpe)(2)] complex exhibits the ability to induce DNA-protein cross-links. The results suggest a different mechanism of action of this compound in comparison to cis-DDP. It seems that trans geometry and the presence of two diethyl (pyridin-4-ylmethyl)phosphates as non-leaving ligands can determine dissimilar properties of the adducts formed on DNA and the different mechanism of action of trans-[PtCl(2)(4-pmOpe)(2)] and in consequence the efficacy in killing cancer cells.

• Authors: Ksenia Matlawska-Wasowska, Katarzyna Rainczuk, Urszula Kalinowska-Lis, Regina Osiecka, Justyn Ochocki
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 168 Issue 2 Pg. 135-42 (Jun 30 2007) ISSN: 0009-2797 [Print] Ireland
• PMID: 17499650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Neoplasm
• Organophosphates
• Organoplatinum Compounds
• diethyl (pyridin-4-ylmethyl)phosphate
• Trypan Blue

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Comet Assay
• DNA Damage
• DNA Repair
• DNA, Neoplasm (drug effects, genetics)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Organophosphates (pharmacology)
• Organoplatinum Compounds (pharmacology)
• Trypan Blue (chemistry)