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Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model

Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model
Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model
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 [14C]-labelled [PtCl2(en)] (where en stands for ethane-1,2-diamine) and cis,trans-[PtCl2(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.
cisplatin, convection, diffusion, drug delivery, multicell, layer, 3D tumour model
0007-0920
194-200
Modok, S.
02128ba2-7993-437a-88f8-82e96b7d1754
Scott, R.
96283dba-5cb5-4ab5-9bbe-e368b68ca406
Alderden, R.A.
a785bc77-f0e9-4231-946a-edb122e4c457
Hall, M.D.
8c57d730-dc73-4365-a56b-1682f3165eb6
Mellor, H.R.
e43d63bc-4f3e-4c26-a3c8-025ef74f1ced
Bohic, S.
d1b92287-65af-4e00-a0a2-b20b8cbbf202
Roose, Tina
3581ab5b-71e1-4897-8d88-59f13f3bccfe
Hambley, T.W.
6093068e-7a96-4010-9944-a6c4f93f5254
Callaghan, R.
ecd0a8b9-f547-4d36-b020-e11ef9ef5e20
Modok, S.
02128ba2-7993-437a-88f8-82e96b7d1754
Scott, R.
96283dba-5cb5-4ab5-9bbe-e368b68ca406
Alderden, R.A.
a785bc77-f0e9-4231-946a-edb122e4c457
Hall, M.D.
8c57d730-dc73-4365-a56b-1682f3165eb6
Mellor, H.R.
e43d63bc-4f3e-4c26-a3c8-025ef74f1ced
Bohic, S.
d1b92287-65af-4e00-a0a2-b20b8cbbf202
Roose, Tina
3581ab5b-71e1-4897-8d88-59f13f3bccfe
Hambley, T.W.
6093068e-7a96-4010-9944-a6c4f93f5254
Callaghan, R.
ecd0a8b9-f547-4d36-b020-e11ef9ef5e20

Modok, S., Scott, R., Alderden, R.A., Hall, M.D., Mellor, H.R., Bohic, S., Roose, Tina, Hambley, T.W. and Callaghan, R. (2007) Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model. British Journal of Cancer, 97 (2), 194-200. (doi:10.1038/sj.bjc.6603854).

Record type: Article

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 [14C]-labelled [PtCl2(en)] (where en stands for ethane-1,2-diamine) and cis,trans-[PtCl2(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.

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More information

Published date: 16 July 2007
Keywords: cisplatin, convection, diffusion, drug delivery, multicell, layer, 3D tumour model

Identifiers

Local EPrints ID: 145141
URI: http://eprints.soton.ac.uk/id/eprint/145141
ISSN: 0007-0920
PURE UUID: 39887988-c6ec-4b43-b778-156808dc0a8b
ORCID for Tina Roose: ORCID iD orcid.org/0000-0001-8710-1063

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Date deposited: 09 Jun 2010 12:17
Last modified: 09 Jan 2022 03:29

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Contributors

Author: S. Modok
Author: R. Scott
Author: R.A. Alderden
Author: M.D. Hall
Author: H.R. Mellor
Author: S. Bohic
Author: Tina Roose ORCID iD
Author: T.W. Hambley
Author: R. Callaghan

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