Mj. Mckeage et al., Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes, CANC CHEMOT, 46(5), 2000, pp. 343-350
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.