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dc.contributor.authorMcKeage, MJ
dc.contributor.authorBerners-Price, SJ
dc.contributor.authorGalettis, P
dc.contributor.authorBowen, RJ
dc.contributor.authorBrouwer, W
dc.contributor.authorDing, L
dc.contributor.authorZhuang, L
dc.contributor.authorBaguley, BC
dc.date.accessioned2017-09-24T23:19:21Z
dc.date.available2017-09-24T23:19:21Z
dc.date.issued2000
dc.date.modified2010-07-26T06:51:56Z
dc.identifier.issn0344-5704
dc.identifier.doi10.1007/s002800000166
dc.identifier.urihttp://hdl.handle.net/10072/3244
dc.description.abstractPurpose: The lipophilic cation [Au(I)(dppe)2]+ [where dppe is 1,2-bis(diphenylphosphino)ethane] has previously demonstrated potent in vitro antitumour activity. We wished to determine the physicochemical basis for the cellular uptake of this drug, as well as of analogues including the 1:2 adducts of Au(I) with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype; n=2, 3 and 4), and to compare in vitro and in vivo antitumour activity. Methods and results: Logarithmic IC50 values for the CH-1 cell line bore a parabolic dependence on drug lipophilicity, as measured either by high-performance liquid chromatography or by n-octanol-water partition. Cellular uptake of drug, as measured by inductively coupled plasma mass spectrometry, varied by over three orders of magnitude over the series. Logarithmic uptake had a parabolic dependence on drug lipophilicity but a linear relationship to logarithmic IC50 values. Free drug concentrations were determined under the culture conditions and logarithmic free drug IC50 values and uptake rates were linearly related to lipophilicity. Uptake of drug in vivo in tissue from murine colon?38 tumours was approximately proportional to the dose administered. Host toxicity varied according to lipophilicity with the most selective compound having an intermediate value. This compound was also the most active of those tested in vivo, giving a growth delay of 9?days following daily intraperitoneal dosing (10?days) at 4?孯l?kg-1?day-1. It was also significantly more active than another lipophilic cation, MKT-077. Conclusions: Alteration of lipophilicity of aromatic cationic antitumour drugs greatly affects cellular uptake and binding to plasma proteins. Changes in lipophilicity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherSpringer-Verlag
dc.publisher.placeGermany
dc.relation.ispartofpagefrom343
dc.relation.ispartofpageto350
dc.relation.ispartofjournalCancer Chemotherapy and Pharmacology
dc.relation.ispartofvolume46
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchHistory, heritage and archaeology
dc.subject.fieldofresearchcode3214
dc.subject.fieldofresearchcode43
dc.titleRole of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.date.issued2000
gro.hasfulltextNo Full Text
gro.griffith.authorBerners-Price, Sue J.


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