Hypoxanthine transport in human tumour cell lines. Relationship to the inhibition of hypoxanthine rescue by dipyridamole

Hypoxanthine (HPX) uptake was investigated in four human tumour cell lines previously characterised as being sensitive (ds: A549 and MCF7) or insensit ive (di: COR-L23 and T-47D) to dipyridamole (DP)-induced inhibition of HPX rescue from antipurine antifolate-induced growth inhibition. The aim of the study was to determine the mechanism underlying the differential sensitivi ty of HPX rescue to DP. The time-course of HPX uptake in the two ds cell li nes was different in comparison to the two di cell lines. The initial rate of HPX uptake in the di cell lines was more rapid than in the ds cell lines such that at 60 sec the amount of HPX taken up by the former was 2-6 times higher than that taken up by the later. The K-i and T-max for HPX transpor t in di COR-L23 cells were 870 muM and 4.75 muM/10(6) cells/min and 1390 mu M and 1.78 muM/10(6) cells/min in ds A549 cells. HPX transport was not sodi um-dependent in these cells. Equilibrative nucleoside transporter 2 (ENT2)- mediated thymidine transport was also higher in di cells. DP inhibited HPX uptake into ds cell lines by greater than or equal to 48% and by less than or equal to 20% in the di cell lines. Competition studies with HPX and thym idine transport via ENT2 indicated an overlap between nucleoside and nucleo base transport transporters in the breast cancer cell lines (MCF7 and T-47D ). These studies showed that more rapid and extensive HPX uptake, as well a s reduced sensitivity to DP inhibition, is associated with the inability of DP to prevent HPX rescue from antipurine antifolate-induced growth inhibit ion in certain human tumour cell lines. (C) 2001 Elsevier Science Inc. All rights reserved.