Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes

Purpose: The lipophilic cation [Au(I)(dppe)(2)](+) [where dppe is 1,2-bis(d iphenylphosphino)ethane] has previously demonstrated potent in vitro antitu mour activity. We wished to determine the physicochemical basis for the cel lular uptake of this drug, as well as of analogues including the 1:2 adduct s of Au(I) with 1,2-bis(din-pyridylphosphino)ethane (dnpype; n = 2, 3 and 4 ), and to compare in vitro and in vivo antitumour activity. Methods ann res ults: Logarithmic IC50 values for the CH-1 cell line bore a parabolic depen dence 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 t hree orders of magnitude over the series. Logarithmic uptake had a paraboli c dependence on drug lipophilicity but a linear relationship to logarithmic IC50 values. Free drug concentrations were determined under the culture co nditions and logarithmic free drug IC50 values and uptake rates were linear ly related to lipophilicity. Uptake of drug in vivo in tissue from murine c olon 38 tumours was approximately proportional to the dose administered. Ho st toxicity varied according to lipophilicity with the most selective compo und 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 intr aperitoneal dosing (10 days) at 4 mu mol kg(-1) day(-1). It was also signif icantly more active than another lipophilic cation, MKT-077. Conclusions: A lteration of lipophilicity of aromatic cationic antitumour drugs greatly af fects cellular uptake and binding to plasma proteins. Changes in lipophilic ity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.