Fluoropyrimidine activity (WP1601)

The main mechanism of 5-FU activation is conversion to fluorodeoxyuridine monophosphate (FdUMP) which inhibits the enzyme thymidylate synthase (TYMS), an important part of the folate-homocysteine cycle and purine and pyrimidine synthesis The conversion of 5-FU to FdUMP can occur via thymidylate phosphorylase (TYMP) to fluorodeoxyuridine (FUDR) and then by the action of thymidine kinase to FdUMP or indirectly via fluorouridine monophosphate (FUMP) or fluroridine (FUR) to fluorouridine diphosphate (FUDP) and then ribonucleotide reductase action to FdUDP and FdUMP. FUDP and FdUDP can also be converted to FUTP and FdUTP and incorporated into RNA and DNA respectively which also contributes to the pharmacodynamic actions of fluoropyrimidines. Sources: [https://www.pharmgkb.org/pathway/PA150653776 PharmGKB:Fluoropyrimidine Pharmacokinetics], [https://www.pharmgkb.org/pathway/PA165291507 PharmGKB:Fluoropyrimidine Pharmacodynamics], [http://en.wikipedia.org/wiki/Fluorouracil Wikipedia:Fluorouracil] Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1601 CPTAC Assay Portal]
last edited


AlexanderPico, MaintBot, Khanspers, Anwesha, Evelo, Egonw, AaronCaine, DeSl, Mkutmon, Etaglobin, Fehrhart, and Eweitz

Cited In


Homo sapiens


CPTAC Diseases


Pathway Ontology: drug pathway cancer pathway

Disease Ontology: cancer

Cell Type Ontology: hepatocyte


Label Type Compact Identifier
5-fluorouracil (5-FU) Metabolite chebi:46345
Capecitabine Metabolite chebi:31348
FUR Metabolite None
5-dFUR Metabolite wikidata:Q1253473
dTMP Metabolite hmdb:HMDB0001227
FUTP Metabolite pubchem.compound:10255482
FUPA Metabolite pubchem.compound:151244
FdUTP Metabolite pubchem.compound:503023
UPP1 GeneProduct ncbigene:7378
TK1 GeneProduct ncbigene:7083
5-hydroxytegafur Metabolite None
SLC22A7 GeneProduct ncbigene:10864
ABCC5 GeneProduct ncbigene:10057
DHFR GeneProduct ncbigene:1719
CDA GeneProduct ncbigene:978
TDG GeneProduct ncbigene:6996
Tegafur Metabolite chemspider:5193
Leucovorin Metabolite pubchem.compound:135403648
ABCC3 GeneProduct ncbigene:8714
UPP2 GeneProduct ncbigene:151531
DPYD GeneProduct ncbigene:1806
MIR29C GeneProduct ensembl:ENSG00000284214
UPP1 GeneProduct ncbigene:7378
FPGS GeneProduct ncbigene:2356
ABCC4 GeneProduct ncbigene:10257
SMUG1 GeneProduct ncbigene:23583
TYMS GeneProduct ncbigene:7298
TYMP GeneProduct ncbigene:1890
MTHFR GeneProduct ncbigene:4524
dUMP Metabolite hmdb:HMDB0001409
DPYS GeneProduct ncbigene:1807
RRM1 GeneProduct ncbigene:6240
UMPS GeneProduct ncbigene:7372
DNA Repair Pathway wikipathways:WP1805
5-FU Metabolite chebi:46345
FUDP Metabolite pubchem.compound:46936877
UCK1 GeneProduct ncbigene:83549
XRCC3 GeneProduct ncbigene:7517
FUMP Metabolite cas:796-66-7
ERCC2 GeneProduct ncbigene:2068
Folate Cycle Pathway wikipathways:WP176
CES1 GeneProduct ncbigene:1066
UCK2 GeneProduct ncbigene:7371
5-FU Metabolite chebi:46345
FBAL Metabolite pubchem.compound:13351
FUTP Metabolite pubchem.compound:10255482
5,10-Methylenetetrahydrofolate Metabolite chemspider:97272
FdUTP Metabolite pubchem.compound:503023
GGH GeneProduct ncbigene:8836
CYP2A6 GeneProduct ncbigene:1548
FdUDP Metabolite pubchem.compound:53882537
ABCG2 GeneProduct ncbigene:9429
5-FU Metabolite chebi:46345
Dihydrofolate Metabolite hmdb:HMDB0001056
TP53 GeneProduct ncbigene:7157
RRM2 GeneProduct ncbigene:6241
Apoptosis Pathway wikipathways:WP254
FUDR Metabolite wikidata:Q5462356
FdUMP Metabolite pubchem.compound:8642
FdUMP Metabolite pubchem.compound:8642
5-dFCR Metabolite pubchem.compound:10037499
SLC29A1 GeneProduct ncbigene:2030
UPB1 GeneProduct ncbigene:51733
UPP2 GeneProduct ncbigene:151531
TYMP GeneProduct ncbigene:1890
PPAT GeneProduct ncbigene:5471
ABCC4 GeneProduct ncbigene:10257
DHFU Metabolite pubchem.compound:121997
CES2 GeneProduct ncbigene:8824


  1. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989 Apr;16(4):215–37. PubMed Europe PMC Scholia
  2. Sobrero AF, Aschele C, Bertino JR. Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation. J Clin Oncol. 1997 Jan;15(1):368–81. PubMed Europe PMC Scholia
  3. Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998 Jul;34(8):1274–81. PubMed Europe PMC Scholia
  4. Cao D, Russell RL, Zhang D, Leffert JJ, Pizzorno G. Uridine phosphorylase (-/-) murine embryonic stem cells clarify the key role of this enzyme in the regulation of the pyrimidine salvage pathway and in the activation of fluoropyrimidines. Cancer Res. 2002 Apr 15;62(8):2313–7. PubMed Europe PMC Scholia
  5. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330–8. PubMed Europe PMC Scholia
  6. van Kuilenburg ABP, Meinsma R, Zonnenberg BA, Zoetekouw L, Baas F, Matsuda K, et al. Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. Clin Cancer Res. 2003 Oct 1;9(12):4363–7. PubMed Europe PMC Scholia
  7. Wang W, Cassidy J, O’Brien V, Ryan KM, Collie-Duguid E. Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167–76. PubMed Europe PMC Scholia
  8. Gmeiner WH. Novel chemical strategies for thymidylate synthase inhibition. Curr Med Chem. 2005;12(2):191–202. PubMed Europe PMC Scholia
  9. Kidd EA, Yu J, Li X, Shannon WD, Watson MA, McLeod HL. Variance in the expression of 5-Fluorouracil pathway genes in colorectal cancer. Clin Cancer Res. 2005 Apr 1;11(7):2612–9. PubMed Europe PMC Scholia
  10. Kobayashi Y, Ohshiro N, Sakai R, Ohbayashi M, Kohyama N, Yamamoto T. Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharmacol. 2005 May;57(5):573–8. PubMed Europe PMC Scholia
  11. Marsh S. Thymidylate synthase pharmacogenetics. Invest New Drugs. 2005 Dec;23(6):533–7. PubMed Europe PMC Scholia
  12. Boyer J, Allen WL, McLean EG, Wilson PM, McCulla A, Moore S, et al. Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765–77. PubMed Europe PMC Scholia
  13. De Angelis PM, Svendsrud DH, Kravik KL, Stokke T. Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. PubMed Europe PMC Scholia
  14. Wu X, Gu J, Wu T-T, Swisher SG, Liao Z, Correa AM, et al. Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. J Clin Oncol. 2006 Aug 10;24(23):3789–98. PubMed Europe PMC Scholia
  15. An Q, Robins P, Lindahl T, Barnes DE. 5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity. Cancer Res. 2007 Feb 1;67(3):940–5. PubMed Europe PMC Scholia
  16. Ruzzo A, Graziano F, Loupakis F, Santini D, Catalano V, Bisonni R, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharmacogenomics J. 2008 Aug;8(4):278–88. PubMed Europe PMC Scholia
  17. Tsujie M, Nakamori S, Nakahira S, Takahashi Y, Hayashi N, Okami J, et al. Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer. Anticancer Res. 2007;27(4B):2241–9. PubMed Europe PMC Scholia
  18. Gusella M, Padrini R. G>C SNP of thymidylate synthase with respect to colorectal cancer. Pharmacogenomics. 2007 Aug;8(8):985–96. PubMed Europe PMC Scholia
  19. Sakamoto E, Tsukioka S, Oie S, Kobunai T, Tsujimoto H, Sakamoto K, et al. Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity. Biochem Biophys Res Commun. 2008 Jan 25;365(4):801–7. PubMed Europe PMC Scholia
  20. Thomas HR, Ezzeldin HH, Guarcello V, Mattison LK, Fridley BL, Diasio RB. Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism. Pharmacogenet Genomics. 2007 Nov;17(11):973–87. PubMed Europe PMC Scholia
  21. Yen-Revollo JL, Goldberg RM, McLeod HL. Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines? Clin Cancer Res. 2008 Jan 1;14(1):8–13. PubMed Europe PMC Scholia
  22. Huang M-Y, Fang W-Y, Lee S-C, Cheng T-L, Wang J-Y, Lin S-R. ERCC2 2251A>C genetic polymorphism was highly correlated with early relapse in high-risk stage II and stage III colorectal cancer patients: a preliminary study. BMC Cancer. 2008 Feb 12;8:50. PubMed Europe PMC Scholia
  23. Huang Z-H, Hua D, Li L-H, Zhu J-D. Prognostic role of p53 codon 72 polymorphism in gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy. J Cancer Res Clin Oncol. 2008 Oct;134(10):1129–34. PubMed Europe PMC Scholia
  24. Sengupta S, den Boon JA, Chen I-H, Newton MA, Stanhope SA, Cheng Y-J, et al. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5874–8. PubMed Europe PMC Scholia
  25. Nordgard SH, Alnaes GIG, Hihn B, Lingjaerde OC, Liestøl K, Tsalenko A, et al. Pathway based analysis of SNPs with relevance to 5-FU therapy: relation to intratumoral mRNA expression and survival. Int J Cancer. 2008 Aug 1;123(3):577–85. PubMed Europe PMC Scholia
  26. Jensen SA, Vainer B, Witton CJ, Jørgensen JT, Sørensen JB. Prognostic significance of numeric aberrations of genes for thymidylate synthase, thymidine phosphorylase and dihydrofolate reductase in colorectal cancer. Acta Oncol. 2008;47(6):1054–61. PubMed Europe PMC Scholia
  27. Yuan J, Lv H, Peng B, Wang C, Yu Y, He Z. Role of BCRP as a biomarker for predicting resistance to 5-fluorouracil in breast cancer. Cancer Chemother Pharmacol. 2009 May;63(6):1103–10. PubMed Europe PMC Scholia
  28. Yuan J-H, Cheng J-Q, Jiang L-Y, Ji W-D, Guo L-F, Liu J-J, et al. Breast cancer resistance protein expression and 5-fluorouracil resistance. Biomed Environ Sci. 2008 Aug;21(4):290–5. PubMed Europe PMC Scholia
  29. Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009 Jan;136(1):187–95. PubMed Europe PMC Scholia
  30. Hagmann W, Jesnowski R, Faissner R, Guo C, Löhr JM. ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology. 2009;9(1–2):136–44. PubMed Europe PMC Scholia
  31. Iacopetta B, Kawakami K, Watanabe T. Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup? Int J Clin Oncol. 2008 Dec;13(6):498–503. PubMed Europe PMC Scholia
  32. De Mattia E, Toffoli G. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer. 2009 May;45(8):1333–51. PubMed Europe PMC Scholia
  33. Behera RK, Nayak R. Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561–7. PubMed Europe PMC Scholia
  34. Karasawa H, Miura K, Fujibuchi W, Ishida K, Kaneko N, Kinouchi M, et al. Down-regulation of cIAP2 enhances 5-FU sensitivity through the apoptotic pathway in human colon cancer cells. Cancer Sci. 2009 May;100(5):903–13. PubMed Europe PMC Scholia
  35. Peters EJ, Kraja AT, Lin SJ, Yen-Revollo JL, Marsh S, Province MA, et al. Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity. Pharmacogenet Genomics. 2009 May;19(5):399–401. PubMed Europe PMC Scholia
  36. Humeniuk R, Menon LG, Mishra PJ, Gorlick R, Sowers R, Rode W, et al. Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Mol Cancer Ther. 2009 May;8(5):1037–44. PubMed Europe PMC Scholia
  37. Kunz C, Focke F, Saito Y, Schuermann D, Lettieri T, Selfridge J, et al. Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. PLoS Biol. 2009 Apr 28;7(4):e91. PubMed Europe PMC Scholia