title: Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model.
abstract: Four-coordinate (Pt(II)) platinum-based anticancer drugs are widely used in primary or palliative chemotherapy and produce considerable efficacy in certain clinical applications, for example testicular cancer. However, in many cancers the Pt(II) drugs are beset by poor efficacy mainly due to suboptimal pharmacokinetic properties. Consequently, the six-coordinate (Pt(IV)) class of Pt drugs were developed to improve platinum efficacy by (i) increasing stability, (ii) reducing reactivity, (iii) increasing lipophilicity, and (iv) nuclear targeting. However, comparatively little information is available on the pharmacokinetic properties of these compounds within solid tumour tissue. In the present study, the distribution and fluxes of [(14)C]-labelled [PtCl(2)(en)] (where en stands for ethane-1,2-diamine) and cis,trans-[PtCl(2)(OH)(2)(en)] drugs were determined in the multicell layer (MCL) tumour model comprising colon cancer cells. Flux data were analysed by mathematical modelling of drug diffusion and cellular uptake in the transport system. The flux of the Pt(IV) compound through the MCL was not significantly different to that of the Pt(II) drug nor were the diffusion coefficient or tissue uptake; the latter confirmed with elemental imaging analysis by synchrotron radiation induced X-ray emission. However, the flux of the Pt(IV) through the MCL was increased by hydrostatic pressure, thereby demonstrating the potential to target cancer cells further away from the vessels with six-coordinate platinum drugs.
authors.affiliation: Oxford Drug Resistance Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Level 4, The John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: S
authors.initials: S
authors.lastname: Modok
authors.forename: R
authors.initials: R
authors.lastname: Scott
authors.forename: R A
authors.initials: RA
authors.lastname: Alderden
authors.forename: M D
authors.initials: MD
authors.lastname: Hall
authors.forename: H R
authors.initials: HR
authors.lastname: Mellor
authors.forename: S
authors.initials: S
authors.lastname: Bohic
authors.forename: T
authors.initials: T
authors.lastname: Roose
authors.forename: T W
authors.initials: TW
authors.lastname: Hambley
authors.forename: R
authors.initials: R
authors.lastname: Callaghan
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D001692:Biological Transport; D045744:Cell Line, Tumor; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds