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-fluorouracil by a number of different agents has permitted a significant increase in the response rate to this agent, particularly for colorectal cancers. Brequinar, a noncompetitive inhibitor of mitochondrial dihydroorotate dehydrogenase has been shown to achieve a tumor-specific modulation of the therapeutic effect of 5-fluorouracil. A selective decrease of uridine nucleotide pools in Colon tumor 38 compared to normal tissues 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 with Brequinar 4 and 24 h prior to administration of [3H]fluorouracil significantly increased incorporation of the fluoropyrimidine into Colon 38 tumor RNA, while minimal effects were seen in normal tissues of C57/BL6 mice. Brequinar (15, 30, and 50 mg/kg) was administered 4 h prior to fluorouracil (85 mg/kg) on a weekly basis in Colon 38-bearing mice. All combinations potentiated 5-fluorouracil antitumor activity and the lowest dose of Brequinar (15 mg/kg) showed a reduced toxicity (weight loss) compared to the same dose of 5-fluorouracil as a single agent. When Brequinar preceded fluorouracil by 24 h, greater toxicity and less antitumor activity were observed. A comparison of the optimal Brequinar-fluorouracil regimen with a previously optimized N-(phosphonoacetyl)-L-aspartic acid-fluorouracil combination in Colon 38 tumor indicated that Brequinar-fluorouracil was more effective and less toxic.
Pizzorno
G
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Department of Pharmacology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Wiegand
R A
RA
Lentz
S K
SK
Handschumacher
R E
RE
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism*; D014500:Uracil Nucleotides / Q000378:metabolism*; D014529:Uridine / Q000378:metabolism*; D011798:Quinaldines
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D005472:Fluorouracil; D013940:Thymidylate Synthase; D014500:Uracil Nucleotides; D014529:Uridine; C046943:brequinar; D011798:Quinaldines