Mechanism of synergy between N-phosphonacetyl-L-aspartate and dipyridamole in a human ovarian carcinoma cell line.
Previous results from our laboratory have shown that 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 microM) 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 microM failed to rescue the ovarian cells from the drug combination, and combining two nucleosides together did not antagonize PALA and PALA plus DP activity to any greater extent. Cellular nucleotide pool analysis by anion-exchange high-performance liquid chromatography revealed that dipyridamole further reduced the already depressed uridine triphosphate and cytidine triphosphate pools of cells exposed to PALA, while the guanosine triphosphate pool was slightly elevated. Uridine supplementation resulted in partial replenishment of the uridine triphosphate and cytidine triphosphate pools, but the absolute levels remained below control 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.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D004176:Dipyridamole / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D009711:Nucleotides / Q000032:analysis; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D014529:Uridine / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D009711:Nucleotides; D009943:Organophosphorus Compounds; D001224:Aspartic Acid; D004176:Dipyridamole; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D014529:Uridine