Pyrimidine studies. III. Effect of several compounds with antitumor activity on utilization of precursors for synthesis of nucleic acid pyrimidines.

Addition of amethopterin to an incubation medium containing slices of the human tumor transplants H.S. #1 and II.Ep. #3 decreased selectively the utilization of orotie acid-C 1~ for the synthesis of DNA thymine. A substantially larger depression of the specific activity of DNA thymine was observed upon addition of both amethopterin and 5-bromouridine to the incubation medium than upon addition of amethopterin or 5-bromouridine. Seven hours following in vivo administration of amethopterin, the utilization of ureidosueeinie aeid-C TM for the synthesis of DNA thymine was decreased to a greater extent than for the other nucleic acid pyrimidines in tumor (H.S. #l), liver, and intestine. Substantial suppression of the utilization of orotie aeid-C ~ for I)NA thymine synthesis in H.S. #1 tumor slices was observed when the incubation mixture contained 5-fluorouridine and 5-fluorodeoxyuridine. Under these conditions, the utilization of thymidine-C ~ for DNA thymine synthesis was enhanced. Seven hours following administration of 5-fluorouracil (50 and 150 mg/kg) and 5fluoroorotie acid (67 mg/kg) to rats bearing H.S. #1 tumors, the utilization of orotie aeid-C TM for DNA thymine was depressed by a greater factor in liver DNA than in tumor or intestine. Other compounds studied in vivo in a search for selective effects on pyrimidine metabolism included azaserine, urethan, and N-methylformamide.