BREQUINAR POTENTIATES 5-FLUOROURACIL ANTITUMOR-ACTIVITY IN A MURINE MODEL COLON-38 TUMOR BY TISSUE-SPECIFIC MODULATION OF URIDINE NUCLEOTIDE POOLS

Modulation of pyrimidine metabolism or the metabolic fate of 5-fluorou racil by a number of different agents has permitted a significant incr ease in the response rate to this agent, particularly for colorectal c ancers. Brequinar, a noncompetitive inhibitor of mitochondrial dihydro orotate dehydrogenase has been shown to achieve a tumor-specific modul ation of the therapeutic effect of 5-fluorouracil. A selective decreas e of uridine nucleotide pools in Colon tumor 38 compared to normal tis sues of C57/BL6 mice was observed after Brequinar administration. This effect was achieved with very low nontherapeutic doses of Brequinar ( 8 to 27% of the maximum tolerated dose in this model). Pretreatment wi th Brequinar 4 and 24 h prior to administration of [H-3]fluorouracil s ignificantly increased incorporation of the fluoropyrimidine into Colo n 38 tumor RNA, while minimal effects were seen in normal tissues of C 57/BL6 mice. Brequinar (15, 30, and 50 mg/kg) was administered 4 h pri or to fluorouracil (85 mg/kg) on a weekly basis in Colon 38-bearing mi ce. All combinations potentiated 5-fluorouracil antitumor activity and the lowest dose of Brequinar (15 mg/kg) showed a reduced toxicity (we ight loss) compared to the same dose of 5-fluorouracil as a single age nt. When Brequinar preceded fluorouracil by 24 h, greater toxicity and less antitumor activity were observed. A comparison of the optimal Br equinar-fluorouracil regimen with a previously optimized N-(phosphonoa cetyl)-L-aspartic acid-fluorouracil combination in Colon 38 tumor indi cated that Brequinar-fluorouracil was more effective and less toxic.