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Literature summary extracted from

  • Tampellini, M.; Bironzo, P.; Di Maio, M.; Scagliotti, G.V.
    Thymidine phosphorylase the unforeseen driver in colorectal cancer treatment? (2018), Future Oncol., 14, 1223-1231 .
    View publication on PubMed

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.4.2.4 5-fluorouracil 5FU, 5-fluorouracil pharmacodynamics, overview. 5FU catabolism is driven by the activity of dihydropyrimidine dehydrogenase (DPD). The expression of the enzymes orotate phosphoribosyl transferase (OPRT), TK, TP, TS and DPD has been demonstrated to influence 5FU activity both in in vitro and in vivo models. 5-Fluoro-2'-deoxyuridine (FUdR), an active antiblastic drug as it can be converted to FdUMP by thymidine kinase (TK), resulting in thymidylate synthase (TS) blockade. FUdR can be hydrolyzed by TP completing the three-step process from capecitabine to 5FU Homo sapiens
2.4.2.4 TAS-102 is a combination of trifluridine (FTD, a fluorinated thymidine analogue) and tipiracil hydrochloride (TPI, a TP inhibitor) at a 1:0.5 molar ratio. The FTD monophosphate metabolite trifluoromethyl deoxyuridine 5'-monophosphate inhibits TS by binding to its active site, but the inhibition is rapidly reversible. Phosphorylation of trifluoromethyl deoxyuridine 5'-monophosphate results in the formation of trifluoromethyl deoxyuridine 5'-triphosphate that is misincorporated into DNA. Importantly, the concentration of FTD incorporated into DNA is approximately 300fold higher than that of 5FU. FTD is rapidly degraded by TP to its inactive metabolite (5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione). Thus, the main mechanism of action of TAS-102 is its misincorporation into DNA. Tipiracil inhibits the main catabolic pathway of the drug, thus enhancing its half-life and cytotoxicity Homo sapiens
2.4.2.4 tipiracil hydrochloride TPI Homo sapiens
2.4.2.4 trifluridine FTD, is rapidly degraded by TP to its inactive metabolite, 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.4.2.4 thymidine + phosphate Homo sapiens
-
 thymine + 2-deoxy-alpha-D-ribose 1-phosphate
-
 r

Organism

EC Number Organism UniProt Comment Textmining
2.4.2.4 Homo sapiens P19971
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.4.2.4 colorectal cancer cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.4.2.4 thymidine + phosphate
-
 Homo sapiens thymine + 2-deoxy-alpha-D-ribose 1-phosphate
-
 r

Expression

EC Number Organism Comment Expression
2.4.2.4 Homo sapiens EGF receptor inhibition may lead to TP overexpression, and tissue hypoxia secondary to low hemoglobin levels may induce TP overexpression up

General Information

EC Number General Information Comment Organism
2.4.2.4 malfunction EGF receptor inhibition may lead to TP overexpression, which decreases the efficacy of infusional 5-fluorouracil (5FU) regimens, while enhancing that of bolus schedules. Tissue hypoxia secondary to low hemoglobin levels may induce TP overexpression, and subsequently, a relative resistance to infusional 5FU Homo sapiens
2.4.2.4 physiological function thymidine phosphorylase (TP) is a nucleoside-metabolizing enzyme that plays a key role in 5-fluorouracil (5FU) pharmacokinetics, as well as in the inflammatory response, neoangiogenesis and apoptosis. TP expression is regulated by hypoxia, inflammatory cytokines and antitumoral agents Homo sapiens