In vitro and in vivo properties of novel nucleoside transport inhibitors with improved pharmacological properties that potentiate antifolate activity.
The activity of antimetabolite inhibitors of de novo deoxyribonucleotide biosynthesis can be compromised by the salvage of extracellular preformed nucleosides and nucleobases. Dipyridamole (DP) is a nucleoside transport inhibitor that has been used clinically in an attempt to increase antimetabolite activity; however, DP binds tightly to the serum protein alpha1-acid glycoprotein (AGP) thereby rendering this therapeutic strategy largely ineffective. Four novel DP analogues (NU3076, NU3084, NU3108, and NU3121) have been developed with substitutions at the 2,6- and 4,8-positions of the pyrimidopyrimidine ring. The novel DP analogues inhibit thymidine (dThd) uptake into L1210 cells in vitro (NU3076 IC(50), 0.25 microM; NU3084 IC(50), 0.27 microM; NU3108 IC(50), 0.31 microM; NU3121 IC(50), 0.26 microM; and DP IC(50), 0.37 microM), but, unlike DP, their activity remains largely unaffected in the presence of 5 mg/ml AGP. The four DP analogues inhibit dThd and hypoxanthine rescue from Alimta (multitargeted antifolate)-induced growth inhibition in A549 and COR L23 human lung carcinoma cell lines in the presence of 2.5 mg/ml AGP, whereas the activity of DP is completely abolished. i.p. administration of 10 mg/kg NU3108, NU3121, and DP produced peak plasma concentrations of 4.4, 2.1, and 6.7 microM, respectively, and levels were sustained above 1 microM for approximately 45 min (DP) and 120 min (NU3108 and NU3121). [3H]thymidine incorporation into COR L23 xenografts grown in CD1 nude mice was reduced by 64% (NU3108), 44% (NU3121), and 65% (DP) 2 h after administration of the nucleoside transport inhibitors. In conclusion, two novel DP analogues (NU3108 and NU3121) have been identified that do not bind to AGP and that display superior pharmacokinetic profiles in comparison to DP and inhibit [3H]thymidine incorporation into human tumor xenografts in vivo.
Smith
P G
PG
Cancer Research Unit, The University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom.
Thomas
H D
HD
Barlow
H C
HC
Griffin
R J
RJ
Golding
B T
BT
Calvert
A H
AH
Newell
D R
DR
Curtin
N J
NJ
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004176:Dipyridamole / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D033703:Nucleoside Transport Proteins; D009961:Orosomucoid / Q000494:pharmacology; D000068437:Pemetrexed; D013763:Tetrahydrofolates / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium; D014407:Tumor Cells, Cultured
C105065:6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid; D002352:Carrier Proteins; D005493:Folic Acid Antagonists; D005971:Glutamates; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D009961:Orosomucoid; D013763:Tetrahydrofolates; D000068437:Pemetrexed; D014316:Tritium; D019271:Hypoxanthine; D006147:Guanine; D004176:Dipyridamole; D013936:Thymidine