Pyrimidine nucleosides enhance the efficacy of inhibitors of pyrimidine biosynthesis in cultured hepatocellular carcinoma cells

Abstract

Inhibition of colony formation in cultured hepatocellular carcinoma cells of the rat was used to test the efficacy of inhibitors of de novo pyrimidine biosynthesis as potential anti-cancer drugs. N-(phosphonacetyl)-L-aspartic acid (PALA) (10 and 100 ωg/ml) and 5-aza-5, 6-dihydroorotic acid (DHOX) (100 ωg/ml) inhibited the formation of colonies and these inhibitions were completely reversed by inclusion of 0.1 mM uridine, the end product of de novo pyrimidine biosynthesis, in the culture medium. With some lots of fetal bovine serum where PALA and DHOX had little effect on inhibiting colony formation, addition of 0.1 mM cytidine restored the inhibitory characteristics of PALA and, to some extent, DHOX. The results demonstrate that cytidine levels modulate the inhibitions of hepatoma colony formation by both PALA and DHOX and that co-administration of these drugs together with cytidine provides a simple expedient to increase drug efficacy.