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Dipyridamole potentiates the in vitro activity of MTA (LY231514) by inhibition of thymidine transport

Lookup NU author(s): Peter Smith, Professor Herbie Newell, Professor Nicola Curtin

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Abstract

The novel pyrrolopyrimidine-based antifolate LY231514 (MTA), inhibits multiple folate-requiring enzymes including thymidylate synthase, glycinamide ribonucleotide formyltransferase and dihydrofolate reductase. Both thymidine and hypoxanthine are required to reverse MTA growth inhibition in leukaemia and colon cancer cells. Prevention of MTA growth inhibition by thymidine and/or hypoxanthine was investigated in two human lung (A549, COR L23) and two breast (MCF7, T47D) tumour cell lines, and the effect of the nucleoside/base transport inhibitor dipyridamole (DP) on thymidine and hypoxanthine rescue defined. MTA IC50 values (continuous exposure three population doublings) were: A549-640 nM, COR L23-28 nM, MCF7-52 nM and T47D-46 nM. Thymidine (1 μM) completely prevented growth inhibition at the MTA IC50 in all cell lines. At 10 x IC50, growth inhibition was only partially reversed by thymidine (≤ 10 μM); both thymidine and hypoxanthine (30 μM) being required for complete reversal, reflecting the multi-targeted nature of MTA. Growth inhibition by MTA was not affected by hypoxanthine alone. A non-toxic concentration (1 μM) of DP prevented thymidine/hypoxanthine rescue of MTA indicating that DP may potentiate MTA activity by preventing nucleoside and/or base salvage. Thymidine transport was inhibited by ≥ 89% by 1 μM DP in all cell lines, whereas hypoxanthine transport was inhibited only in A549 and MCF7 cells. Therefore, prevention of end-product reversal of MTA-induced growth inhibition by DP can be explained by inhibition of thymidine transport alone. (C) 2000 Cancer Research Campaign.


Publication metadata

Author(s): Smith, P., Marshman, E., Newell, D.R., Curtin, N.J.

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2000

Volume: 82

Issue: 4

Pages: 924-930

Print publication date: 01/01/2000

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

URL: http://dx.doi.org/10.1054/bjoc.1999.1020

DOI: 10.1054/bjoc.1999.1020

PubMed id: 10732767


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