Fluoropyrimidine activity (WP1601)

Homo sapiens

Open in new tab Open in NDEx Open in Newt (SBGN)
Download PNG Download SVG Download JSON Download GPML Learn more about Downloads
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]

Authors

Alex Pico , Kristina Hanspers , Anwesha Bohler , Chris Evelo , Egon Willighagen , Aaron Caine , Denise Slenter , Martina Summer-Kutmon , Etaglobin , Friederike Ehrhart , and Eric Weitz

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

CPTAC Diseases ExRNA

Annotations

Cell Type Ontology

hepatocyte

Disease Ontology

cancer

Pathway Ontology

cancer pathway drug pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
5-fluorouracil (5-FU) Metabolite chebi:46345
Capecitabine Metabolite chebi:31348
5-dFUR Metabolite wikidata:Q1253473
dTMP Metabolite hmdb:HMDB0001227
FUTP Metabolite pubchem.compound:10255482
FUPA Metabolite pubchem.compound:151244
FdUTP Metabolite pubchem.compound:503023
Tegafur Metabolite chemspider:5193
Leucovorin Metabolite pubchem.compound:135403648
dUMP Metabolite hmdb:HMDB0001409
5-FU Metabolite chebi:46345
FUDP Metabolite pubchem.compound:46936877
FUMP Metabolite cas:796-66-7
FBAL Metabolite pubchem.compound:13351
5,10-Methylenetetrahydrofolate Metabolite chemspider:97272
FdUDP Metabolite pubchem.compound:53882537
Dihydrofolate Metabolite hmdb:HMDB0001056
FUDR Metabolite wikidata:Q5462356
FdUMP Metabolite pubchem.compound:8642
5-dFCR Metabolite pubchem.compound:10037499
DHFU Metabolite pubchem.compound:121997
UPP1 GeneProduct ncbigene:7378
TK1 GeneProduct ncbigene:7083
SLC22A7 GeneProduct ncbigene:10864
ABCC5 GeneProduct ncbigene:10057
DHFR GeneProduct ncbigene:1719
CDA GeneProduct ncbigene:978
TDG GeneProduct ncbigene:6996
ABCC3 GeneProduct ncbigene:8714
UPP2 GeneProduct ncbigene:151531
DPYD GeneProduct ncbigene:1806
MIR29C GeneProduct ensembl:ENSG00000284214
FPGS GeneProduct ncbigene:2356
ABCC4 GeneProduct ncbigene:10257
SMUG1 GeneProduct ncbigene:23583
TYMS GeneProduct ncbigene:7298
TYMP GeneProduct ncbigene:1890
MTHFR GeneProduct ncbigene:4524
DPYS GeneProduct ncbigene:1807
RRM1 GeneProduct ncbigene:6240
UMPS GeneProduct ncbigene:7372
UCK1 GeneProduct ncbigene:83549
XRCC3 GeneProduct ncbigene:7517
ERCC2 GeneProduct ncbigene:2068
CES1 GeneProduct ncbigene:1066
UCK2 GeneProduct ncbigene:7371
GGH GeneProduct ncbigene:8836
CYP2A6 GeneProduct ncbigene:1548
ABCG2 GeneProduct ncbigene:9429
TP53 GeneProduct ncbigene:7157
RRM2 GeneProduct ncbigene:6241
SLC29A1 GeneProduct ncbigene:2030
UPB1 GeneProduct ncbigene:51733
PPAT GeneProduct ncbigene:5471
CES2 GeneProduct ncbigene:8824

References

  1. Incorporation of 3H-dibromodulcitol and 3H-dianhydrodulcitol into ascites tumor cells. Autoradiographic study. Kopper L, Lapis K, Institóris L. Neoplasma. 1976;23(1):47–52. PubMed Europe PMC Scholia
  2. Clinical pharmacology of 5-fluorouracil. Diasio RB, Harris BE. Clin Pharmacokinet. 1989 Apr;16(4):215–37. PubMed Europe PMC Scholia
  3. Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation. Sobrero AF, Aschele C, Bertino JR. J Clin Oncol. 1997 Jan;15(1):368–81. PubMed Europe PMC Scholia
  4. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. Eur J Cancer. 1998 Jul;34(8):1274–81. PubMed Europe PMC Scholia
  5. 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. Cao D, Russell RL, Zhang D, Leffert JJ, Pizzorno G. Cancer Res. 2002 Apr 15;62(8):2313–7. PubMed Europe PMC Scholia
  6. Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. van Kuilenburg ABP, Meinsma R, Zonnenberg BA, Zoetekouw L, Baas F, Matsuda K, et al. Clin Cancer Res. 2003 Oct 1;9(12):4363–7. PubMed Europe PMC Scholia
  7. Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Wang W, Cassidy J, O’Brien V, Ryan KM, Collie-Duguid E. Cancer Res. 2004 Nov 15;64(22):8167–76. PubMed Europe PMC Scholia
  8. Novel chemical strategies for thymidylate synthase inhibition. Gmeiner WH. Curr Med Chem. 2005;12(2):191–202. PubMed Europe PMC Scholia
  9. Variance in the expression of 5-Fluorouracil pathway genes in colorectal cancer. Kidd EA, Yu J, Li X, Shannon WD, Watson MA, McLeod HL. Clin Cancer Res. 2005 Apr 1;11(7):2612–9. PubMed Europe PMC Scholia
  10. Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). Kobayashi Y, Ohshiro N, Sakai R, Ohbayashi M, Kohyama N, Yamamoto T. J Pharm Pharmacol. 2005 May;57(5):573–8. PubMed Europe PMC Scholia
  11. Thymidylate synthase pharmacogenetics. Marsh S. Invest New Drugs. 2005 Dec;23(6):533–7. PubMed Europe PMC Scholia
  12. Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Boyer J, Allen WL, McLean EG, Wilson PM, McCulla A, Moore S, et al. Cancer Res. 2006 Mar 1;66(5):2765–77. PubMed Europe PMC Scholia
  13. Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. De Angelis PM, Svendsrud DH, Kravik KL, Stokke T. Mol Cancer. 2006 May 18;5:20. PubMed Europe PMC Scholia
  14. Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. Wu X, Gu J, Wu TT, Swisher SG, Liao Z, Correa AM, et al. J Clin Oncol. 2006 Aug 10;24(23):3789–98. PubMed Europe PMC Scholia
  15. 5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity. An Q, Robins P, Lindahl T, Barnes DE. Cancer Res. 2007 Feb 1;67(3):940–5. PubMed Europe PMC Scholia
  16. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Ruzzo A, Graziano F, Loupakis F, Santini D, Catalano V, Bisonni R, et al. Pharmacogenomics J. 2008 Aug;8(4):278–88. PubMed Europe PMC Scholia
  17. Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer. Tsujie M, Nakamori S, Nakahira S, Takahashi Y, Hayashi N, Okami J, et al. Anticancer Res. 2007;27(4B):2241–9. PubMed Europe PMC Scholia
  18. G>C SNP of thymidylate synthase with respect to colorectal cancer. Gusella M, Padrini R. Pharmacogenomics. 2007 Aug;8(8):985–96. PubMed Europe PMC Scholia
  19. Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity. Sakamoto E, Tsukioka S, Oie S, Kobunai T, Tsujimoto H, Sakamoto K, et al. Biochem Biophys Res Commun. 2008 Jan 25;365(4):801–7. PubMed Europe PMC Scholia
  20. Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism. Thomas HR, Ezzeldin HH, Guarcello V, Mattison LK, Fridley BL, Diasio RB. Pharmacogenet Genomics. 2007 Nov;17(11):973–87. PubMed Europe PMC Scholia
  21. Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines? Yen-Revollo JL, Goldberg RM, McLeod HL. Clin Cancer Res. 2008 Jan 1;14(1):8–13. PubMed Europe PMC Scholia
  22. 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. Huang MY, Fang WY, Lee SC, Cheng TL, Wang JY, Lin SR. BMC Cancer. 2008 Feb 12;8:50. PubMed Europe PMC Scholia
  23. Prognostic role of p53 codon 72 polymorphism in gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy. Huang ZH, Hua D, Li LH, Zhu JD. J Cancer Res Clin Oncol. 2008 Oct;134(10):1129–34. PubMed Europe PMC Scholia
  24. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, et al. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5874–8. PubMed Europe PMC Scholia
  25. Pathway based analysis of SNPs with relevance to 5-FU therapy: relation to intratumoral mRNA expression and survival. Nordgard SH, Alnaes GIG, Hihn B, Lingjaerde OC, Liestøl K, Tsalenko A, et al. Int J Cancer. 2008 Aug 1;123(3):577–85. PubMed Europe PMC Scholia
  26. Prognostic significance of numeric aberrations of genes for thymidylate synthase, thymidine phosphorylase and dihydrofolate reductase in colorectal cancer. Jensen SA, Vainer B, Witton CJ, Jørgensen JT, Sørensen JB. Acta Oncol. 2008;47(6):1054–61. PubMed Europe PMC Scholia
  27. Role of BCRP as a biomarker for predicting resistance to 5-fluorouracil in breast cancer. Yuan J, Lv H, Peng B, Wang C, Yu Y, He Z. Cancer Chemother Pharmacol. 2009 May;63(6):1103–10. PubMed Europe PMC Scholia
  28. Breast cancer resistance protein expression and 5-fluorouracil resistance. Yuan JH, Cheng JQ, Jiang LY, Ji WD, Guo LF, Liu JJ, et al. Biomed Environ Sci. 2008 Aug;21(4):290–5. PubMed Europe PMC Scholia
  29. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, et al. Gastroenterology. 2009 Jan;136(1):187–95. PubMed Europe PMC Scholia
  30. ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Hagmann W, Jesnowski R, Faissner R, Guo C, Löhr JM. Pancreatology. 2009;9(1–2):136–44. PubMed Europe PMC Scholia
  31. Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup? Iacopetta B, Kawakami K, Watanabe T. Int J Clin Oncol. 2008 Dec;13(6):498–503. PubMed Europe PMC Scholia
  32. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. De Mattia E, Toffoli G. Eur J Cancer. 2009 May;45(8):1333–51. PubMed Europe PMC Scholia
  33. Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Behera RK, Nayak R. Cancer Invest. 2009 Jun;27(5):561–7. PubMed Europe PMC Scholia
  34. Down-regulation of cIAP2 enhances 5-FU sensitivity through the apoptotic pathway in human colon cancer cells. Karasawa H, Miura K, Fujibuchi W, Ishida K, Kaneko N, Kinouchi M, et al. Cancer Sci. 2009 May;100(5):903–13. PubMed Europe PMC Scholia
  35. Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity. Peters EJ, Kraja AT, Lin SJ, Yen-Revollo JL, Marsh S, Province MA, et al. Pharmacogenet Genomics. 2009 May;19(5):399–401. PubMed Europe PMC Scholia
  36. Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Humeniuk R, Menon LG, Mishra PJ, Gorlick R, Sowers R, Rode W, et al. Mol Cancer Ther. 2009 May;8(5):1037–44. PubMed Europe PMC Scholia
  37. Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. Kunz C, Focke F, Saito Y, Schuermann D, Lettieri T, Selfridge J, et al. PLoS Biol. 2009 Apr 28;7(4):e91. PubMed Europe PMC Scholia