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. 2000 Feb;82(4):924–930. doi: 10.1054/bjoc.1999.1020

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

P G Smith 1, E Marshman 1, D R Newell 1, N J Curtin 1
PMCID: PMC2374405  PMID: 10732767

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 IC50values (continuous exposure three population doublings) were: A549–640 n M, COR L23–28 n M, MCF7–52 n M and T47D–46 n M. Thymidine (1 μM) completely prevented growth inhibition at the MTA IC50in all cell lines. At 10 × 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. © 2000 Cancer Research Campaign

Keywords: dipyridamole, LY231514, thymidine transport, hypoxanthine transport

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Selected References

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