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In vitro and in vivo properties of novel nucleoside transport inhibitors with improved pharmacological properties that potentiate antifolate activity

Lookup NU author(s): Peter Smith, Huw ThomasORCiD, Hannah Barlow, Professor Roger Griffin, Emeritus Professor Bernard Golding, Professor Alan Calvert, Professor Herbie Newell, Professor Nicola CurtinORCiD

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Abstract

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 α1-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 IC50, 0.25 μM; NU3084 IC50, 0.27 μM; NU3108 IC50, 0.31 μM; NU3121 IC50, 0.26 μM; and DP IC50, 0.37 μM), 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 μM, respectively, and levels were sustained above 1 μM for ∼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.

Publication metadata

Author(s): Smith PG, Thomas HD, Barlow HC, Griffin RJ, Golding BT, Calvert AH, Newell DR, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2001

Volume: 7

Issue: 7

Pages: 2105-2113

Print publication date: 01/07/2001

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

URL: http://clincancerres.aacrjournals.org/cgi/content/abstract/7/7/2105

PubMed id: 11448930

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