MECHANISM OF SYNERGY BETWEEN N-PHOSPHONACETYL-L-ASPARTATE AND DIPYRIDAMOLE IN A HUMAN OVARIAN-CARCINOMA CELL-LINE

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (8) , 3598-3604
Abstract
The nucleoside transport inhibitor dipyridamole (DP) markedly augmented both the in vitro and in vivo activities of the pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA). In a human ovarian carcinoma cell line (2008), DP increased the activity of PALA by 1 to 2 logs in growth rate and clonogenic assays while exhibiting no cytotoxicity of its own. The concentration of DP used (1 .mu.m) in these assays resulted in over 80% reduction in uridine uptake in the 2008 cells at the end of 1 h. The activity of PALA and PALA plus DP was completely antagonized by the addition of exogenous uridine in a dose-dependent manner. Addition of other nucleosides to concentrations as high as 1000 .mu.m failed to rescue the ovarian cells from the drug combination, and combining 2 nucleosides together did not antagonize PALA and PALA plus DP activity to any greater extent. Cellular liquid chromatography revealed that dipyridamole further reduced the UTP and CTP pools of cells exposed to PALA, while the GTP pool was slightly elevated. Uridine supplementation resulted in partial replenishment of the UTP and CTP pools, but the absolute levels remained below controls values. The acute drug-induced changes in nucleotide pools in 2008 xenografts growing in athymic mice paralleled those observed in vitro. Evidence presented here supports the ability of DP to potentiate PALA activity against a human ovarian carcinoma cell line. The mechanism of synergy relates to the inhibition of pyrimidine salvage in the tumor cells via the blockade of uridine uptake.