Literature summary for 2.4.2.4 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 .

Search for more literature for 2.4.2.4

Inhibitors

Inhibitors	Comment	Organism	Structure
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
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
tipiracil hydrochloride	TPI	Homo sapiens
trifluridine	FTD, is rapidly degraded by TP to its inactive metabolite, 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione	Homo sapiens

Natural Substrates/ Products (Substrates)

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

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P19971	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
colorectal cancer cell	-	Homo sapiens	-

Substrates and Products (Substrate)

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

Expression

Organism	Comment	Expression
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

General Information	Comment	Organism
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
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

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Release 2023.1 (January 2023)