KEGG   PATHWAY: map01523
Entry
map01523          Global    Pathway                                

Name
Antifolate resistance
Description
Since the 1940s, antifolates have played a pivotal role in drug treatment of malignant, microbial, parasitic and chronic inflammatory diseases. The molecular basis of the anti-proliferative activity of antifolates relies on inhibition of key enzymes in folate metabolism, which results in disruption of purine and thymidylate biosynthesis, inhibition of DNA replication and cell death. The anti-inflammatory properties of antifolate have been most strongly related to its ability to block the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha or interleukin (IL)-1beta. Cells may develop resistance to an antifolate drug by virtue of impaired drug transport into cells, augmented drug export, impaired activation of antifolates through polyglutamylation, augmented hydrolysis of antifolate polyglutamates, increased expression and mutation of target enzymes, and the augmentation of cellular tetrahydrofolate-cofactor pools in cells.
Class
Human Diseases; Drug resistance: antineoplastic
Pathway map
map01523  Antifolate resistance
map01523

Reference
  Authors
Gonen N, Assaraf YG
  Title
Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance.
  Journal
Drug Resist Updat 15:183-210 (2012)
DOI:10.1016/j.drup.2012.07.002
Reference
  Authors
Assaraf YG
  Title
Molecular basis of antifolate resistance.
  Journal
Cancer Metastasis Rev 26:153-81 (2007)
DOI:10.1007/s10555-007-9049-z
Reference
  Authors
Municio C, Soler Palacios B, Estrada-Capetillo L, Benguria A, Dopazo A, Garcia-Lorenzo E, Fernandez-Arroyo S, Joven J, Miranda-Carus ME, Gonzalez-Alvaro I, Puig-Kroger A
  Title
Methotrexate selectively targets human proinflammatory macrophages through a thymidylate synthase/p53 axis.
  Journal
Ann Rheum Dis 75:2157-2165 (2016)
DOI:10.1136/annrheumdis-2015-208736
Reference
  Authors
Wilson PM, Danenberg PV, Johnston PG, Lenz HJ, Ladner RD
  Title
Standing the test of time: targeting thymidylate biosynthesis in cancer therapy.
  Journal
Nat Rev Clin Oncol 11:282-98 (2014)
DOI:10.1038/nrclinonc.2014.51
Reference
  Authors
Fotoohi AK, Albertioni F
  Title
Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells.
  Journal
Leuk Lymphoma 49:410-26 (2008)
DOI:10.1080/10428190701824569
Reference
  Authors
van der Heijden JW, Dijkmans BA, Scheper RJ, Jansen G
  Title
Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs--from bench to bedside.
  Journal
Nat Clin Pract Rheumatol 3:26-34 (2007)
DOI:10.1038/ncprheum0380
Reference
  Authors
Assaraf YG
  Title
The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis.
  Journal
Drug Resist Updat 9:227-46 (2006)
DOI:10.1016/j.drup.2006.09.001
Reference
  Authors
Mauritz R.
  Title
Determinants of antifolate and 5-fluorouracil efficacy
  Journal
Biochemistry
Reference
  Authors
del-Campo LS, Montenegro MF, Saez-Ayala M, Fernandez-Perez MP, Cabezas-Herrera J, Rodriquez-Lopez JN.
  Title
Cellular and molecular mechanisms of methotrexate resistance in melanoma
  Journal
Intech
DOI:10.5772/52414
Reference
  Authors
Walling J
  Title
From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates.
  Journal
Invest New Drugs 24:37-77 (2006)
DOI:10.1007/s10637-005-4541-1
Reference
  Authors
Desmoulin SK, Hou Z, Gangjee A, Matherly LH
  Title
The human proton-coupled folate transporter: Biology and therapeutic applications to cancer.
  Journal
Cancer Biol Ther 13:1355-73 (2012)
DOI:10.4161/cbt.22020
Reference
  Authors
Cheok MH, Evans WE
  Title
Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy.
  Journal
Nat Rev Cancer 6:117-29 (2006)
DOI:10.1038/nrc1800
Reference
  Authors
van der Heijden JW, Assaraf YG, Gerards AH, Oerlemans R, Lems WF, Scheper RJ, Dijkmans BA, Jansen G
  Title
Methotrexate analogues display enhanced inhibition of TNF-alpha production in whole blood from RA patients.
  Journal
Scand J Rheumatol 43:9-16 (2014)
DOI:10.3109/03009742.2013.797490
Reference
PMID:8793930
  Authors
Gorlick R, Goker E, Trippett T, Waltham M, Banerjee D, Bertino JR
  Title
Intrinsic and acquired resistance to methotrexate in acute leukemia.
  Journal
N Engl J Med 335:1041-8 (1996)
DOI:10.1056/NEJM199610033351408
Reference
  Authors
Adjei AA
  Title
Pharmacology and mechanism of action of pemetrexed.
  Journal
Clin Lung Cancer 5 Suppl 2:S51-5 (2004)
DOI:10.3816/CLC.2004.s.003
Reference
  Authors
Zhao R, Goldman ID
  Title
Resistance to antifolates.
  Journal
Oncogene 22:7431-57 (2003)
DOI:10.1038/sj.onc.1206946
Reference
  Authors
Mikkelsen TS, Thorn CF, Yang JJ, Ulrich CM, French D, Zaza G, Dunnenberger HM, Marsh S, McLeod HL, Giacomini K, Becker ML, Gaedigk R, Leeder JS, Kager L, Relling MV, Evans W, Klein TE, Altman RB
  Title
PharmGKB summary: methotrexate pathway.
  Journal
Pharmacogenet Genomics 21:679-86 (2011)
DOI:10.1097/FPC.0b013e328343dd93
Reference
  Authors
Blits M, Jansen G, Assaraf YG, van de Wiel MA, Lems WF, Nurmohamed MT, van Schaardenburg D, Voskuyl AE, Wolbink GJ, Vosslamber S, Verweij CL
  Title
Methotrexate normalizes up-regulated folate pathway genes in rheumatoid arthritis.
  Journal
Arthritis Rheum 65:2791-802 (2013)
DOI:10.1002/art.38094
Reference
  Authors
Majumdar S, Aggarwal BB
  Title
Methotrexate suppresses NF-kappaB activation through inhibition of IkappaBalpha phosphorylation and degradation.
  Journal
J Immunol 167:2911-20 (2001)
DOI:10.4049/jimmunol.167.5.2911
Related
pathway
map00230  Purine metabolism
map00670  One carbon pool by folate
map04064  NF-kappa B signaling pathway
map04144  Endocytosis
KO pathway
ko01523   
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