The mechanism of action of platinum(IV) complexes in ovarian cancer cell lines.
The reduction potentials, lipophilicities, cellular uptake and cytotoxicity have been examined for two series of platinum(IV) complexes that yield common platinum(II) complexes on reduction: cis-[PtCl(4)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OAc)(2)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)], [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)] and cis,trans-[PtCl(2)(OH)(2)(en)] (en=ethane-1,2-diamine, OAc=acetate). As previously reported, the reduction occurs most readily when the axial ligand is chloride and least readily when it is hydroxide. The en series of complexes are marginally more lipophilic than their ammine analogues. The presence of axial chloride or acetate ligands results in a slighter higher lipophilicity compared with the platinum(II) analogue whereas hydroxide ligands lead to a substantially lower lipophilicity. The cellular uptake is similar for the platinum(II) species and their analogous tetrachloro complexes, but is substantially lower for the acetato and hydroxo complexes, resulting in a correlation with the reduction potential. The activities are also correlated with the reduction potentials with the tetrachloro complexes being the most active of the platinum(IV) series and the hydroxo being the least active. These results are interpreted in terms of reduction, followed by aquation reducing the amount of efflux from the cells resulting in an increase in net uptake.
Centre for Heavy Metals Research, School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Matthew D
MD
Hall
Shahriar
S
Amjadi
Mei
M
Zhang
Philip J
PJ
Beale
Trevor W
TW
Hambley
D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004563:Electrochemistry; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000473:pathology*; D017671:Platinum Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
D017671:Platinum Compounds; D002945:Cisplatin