Nj. Curtin et al., Potentiation of the cytotoxicity of thymidylate synthase (TS) inhibitors by dipyridamole analogues with reduced alpha(1)-acid glycoprotein binding, BR J CANC, 80(11), 1999, pp. 1738-1746
Dipyridamole has been shown to enhance the in vitro activity of antimetabol
ite anticancer drugs through the inhibition of nucleoside transport. Howeve
r, the clinical potential of dipyribamole has not been realized because of
the avid binding of the drug to the plasma protein alpha(1)-acid glycoprote
in (AGP). Dipyridamole analogues that retain potent nucleoside transport in
hibitory activity in the presence of AGP are described and their ability to
enhance the growth inhibitory and cytotoxic effects of thymidylate synthas
e (TS) inhibitors has been evaluated. Three dipyridamole analogues (NU3026,
NU3059 and NU3060) were shown to enhance the growth inhibitory activity of
the TS inhibitor CB3717 and block thymidine rescue in L1210 cells. The ext
ent of potentiation at a fixed analogue concentration (10 mu M) was related
to the potency of inhibition of thymidine uptake. A further analogue, NU30
76, was identified; which was more potent than dipyridamole with a K-i valu
e for inhibition of thymidine uptake of 0.1 mu M compared to 0.28 mu M for
dipyridamole. in marked contrast to dipyridamole, inhibition of thymidine u
ptake by NU3076 was not significantly affected by the presence of AGP (5 mg
ml(-1)). NU3076 and dipyridamole produced equivalent potentiation of the c
ytotoxicity of the non-classical antifolate TS inhibitor, nolatrexed, in L1
210 cells with both compounds significantly reducing the LC90 by > threefol
d in the absence of salvageable thymidine. Thymidine rescue of L1210 cells
from nolatrexed cytotoxicity was partially blocked by both 1 mu M NU3076 an
d 1 mu M dipyridamole. NU3076 also caused a significant potentiation of FU
cytotoxicity in L1210 cells. These studies demonstrate that nucleoside tran
sport inhibition can be maintained in the absence of AGP binding with the d
ipyridamole pharmacophore and that such analogues can enhance the cytotoxic
ity of TS inhibitors.