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 insensitive (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 sensitivity of HPX rescue to DP. The time-course of HPX uptake in the two ds cell lines 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(t) and T(max) for HPX transport in di COR-L23 cells were 870 microM and 4.75 microM/10(6) cells/min and 1390 microM and 1.78 microM/10(6) cells/min in ds A549 cells. HPX transport was not sodium-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 > or =48% and by < or =20% in the di cell lines. Competition studies with HPX and thymidine transport via ENT2 indicated an overlap between nucleoside and nucleobase transport transporters in the breast cancer cell lines (MCF7 and T-47D). These studies showed that more rapid and extensive HPX uptake, as well as reduced sensitivity to DP inhibition, is associated with the inability of DP to prevent HPX rescue from antipurine antifolate-induced growth inhibition in certain human tumour cell lines.
Cancer Research Unit, Medical School, University of Newcastle upon Tyne, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK.
E
E
Marshman
G A
GA
Taylor
H D
HD
Thomas
D R
DR
Newell
N J
NJ
Curtin
D000345:Affinity Labels / Q000378:metabolism; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D033705:Equilibrative Nucleoside Transport Proteins; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000345:Affinity Labels; D002352:Carrier Proteins; D033705:Equilibrative Nucleoside Transport Proteins; D005493:Folic Acid Antagonists; D010726:Phosphodiesterase Inhibitors; D019271:Hypoxanthine; D013868:Thioinosine; D004176:Dipyridamole; D012964:Sodium; C001789:4-nitrobenzylthioinosine; D013936:Thymidine