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Fluoropyrimidines are antimetabolite drugs widely used in the treatment of cancer including
colorectal and breast cancer and cancers of the aerodigestive tract. This graphic shows candidate genes
involved in the pharmacokinetics of 5-fluorouracil (5-FU), capecitabine and tegafur.
5-FU is commonly given intravenously where more than 80% of it is metabolized in the liver
[2656050]. Capecitabine is an oral prodrug of 5-FU which passes unaltered through the gut
wall and is converted into 5’dFCR then 5’-deoxy-5-fluorouridine (5’dFUR) in the liver by
carboxylesterase and cytidine deaminase respectively [9849491; 18172246]. 5’dFUR is then
converted to 5-FU via thymidine phosphorylase or uridine phosphorylase [9849491; 11956089].
Tegafur is another prodrug of 5-FU that is converted by CYP2A6 to an unstable intermediate,
5-hydroxytegafur, which spontaneously breaks down to form 5-FU [18172246].
There are several routes for metabolism of 5-FU, some of which lead to activation and
pharmacodynamic actions of the drug. The rate-limiting step of 5-FU catabolism is
dihydropyrimidine dehydrogenase (DPYD) conversion of 5-FU to dihydrofluorouracil (DHFU)
[14555507; 1272473]. DHFU is then converted to fluoro-beta-ureidopropionate (FUPA) and
subsequently to fluoro-beta-alanine (FBAL) by dihydropyrimidinease (DPYS) and beta-ureidopropionase (UPB1),
respectively [14555507]. Deficiency in enzymes in this pathway can result in severe and even fatal 5-FU
toxicity. Several variants in DPYD have been associated with toxicity including (see the DPYD VIP and
curated annotations for more details). Variants in DPYS have also been shown to influence 5-FU toxicity.
A rare variant DPYS:833G>A (DPYS:Gly278Asp) in exon 5 was shown to be the determining variant of severe
toxicity in a Dutch patient receiving 5-FU [14555507]. Variants DPYS:1635delC and DPYS:Leu7Val were shown
in vitro to have reduced activity [18075467]. In order to modulate the activity of fluoropyrimidines,
inhibitors of DPYD such as uracil and eniluracil can be coadministered. This slows the degradation of
5-FU and can improve response rate [12724731].
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.
An important consideration in the use of 5-FU and related drugs is the development of drug
resistance by the tumor. Some mechanisms of resistance involve expression changes in pharmacodynamic
gene candidates (TYMS and P53). Drug resistance can also involve changes in drug transport. There
is conflicting data about the transporters involved in the pharmacokinetics of 5-FU. SLC29A1
expression was not associated with survival in one study of pancreatic tumors [18992248] but
resistance/sensitivity was associated with its expression in another study of pancreatic tumor
cell lines [17695509]. Transport of 5-FU has been reported in an in vitro expression system of
SLC22A7 [15901346]. Several transporters have been implicated in 5-FU resistance including ABCG2
[18820913][18837291], ABCC3, ABCC4 and ABCC5 [19077464]. |
