title: The Role of Fluoropirimidines in Gastrointestinal Tumours: from the Bench to the Bed.
abstract: OBJECTIVE
  Gastrointestinal tumours are one of the most common types of cancer. Therapeutic options include surgery, radiotherapy, local ablation techniques, targeted agents, and chemotherapy. Fluoroprimidines are one of the most active drug families in digestive tumours and remains the cornerstone of the most commonly used chemotherapy schemes.
  
  
  METHODS
  We review the molecular basis of thymidylate synthase inhibition and the mechanisms of action of 5-fluorouracil, next generation oral fluoropyrimidines (capecitabine, tegafur and the latest S-1 and TAS-102) and antifolates.
  
  
  RESULTS
  In addition, mechanisms and biomarkers of resistance and toxicity are explored. Finally, new fluoropyrimidines development and clinical trials ongoing in digestive tumours are reviewed.
  
  
  CONCLUSIONS
  Further research is necessary to avoid resistance mechanisms, improve clinical outcomes and continue reducing toxicities. Until new drugs become available, the optimization of current therapies should be a priority.
authors.affiliation: Medical Oncology Department, Miguel Servet University Hospital, Paseo Isabel la Católica 1-3, 5009, Zaragoza, Spain. jhernandocu@salud.aragon.es.
authors.forename: Jorge
authors.initials: J
authors.lastname: Hernando-Cubero
authors.affiliation: Medical Oncology Department, Vall d´Hebron University Hospital, Vall d´Hebron Institute of Oncology (VHIO), Pg Vall d´Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Matos-García
authors.affiliation: Medical Oncology Department, Miguel Servet University Hospital, Paseo Isabel la Católica 1-3, 5009, Zaragoza, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Alonso-Orduña
authors.affiliation: Medical Oncology Department, Vall d´Hebron University Hospital, Vall d´Hebron Institute of Oncology (VHIO), Pg Vall d´Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Capdevila
mesh_terms: D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D002986:Clinical Trials as Topic; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013941:Thymine; D014271:Trifluridine / Q000494:pharmacology / Q000627:therapeutic use; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); C000600377:TYMS protein, human; D013940:Thymidylate Synthase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; D013941:Thymine; D014271:Trifluridine; D005472:Fluorouracil
keywords: Capecitabine; Fluropyrimidines; Gastrointestinal cancer; S-1, TAS-102; Thymidylate synthase