Pyrimidine nucleosides enhance the efficacy of inhibitors of pyrimidine biosynthesis in cultured hepatocellular carcinoma cells.
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 anticancer drugs. N-(phosphonacetyl)-L-aspartic acid (PALA) (10 and 100 micrograms/ml) and 5-aza-5,6-dihydroorotic acid (DHOX) (100 micrograms/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.
Jacobsen
L B
LB
Department of Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, IN 47907.
Putnam
J E
JE
Sawick
D P
DP
Cassady
J M
JM
Morré
D J
DJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003562:Cytidine / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D009963:Orotic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D011743:Pyrimidines / Q000096:biosynthesis*; D051381:Rats; D014407:Tumor Cells, Cultured; D014529:Uridine / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines; D001224:Aspartic Acid; C026313:dihydro-5-azaorotic acid; D003562:Cytidine; D009963:Orotic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D014529:Uridine