Page 65 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg
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DPWG guideline for DPYD and fluoropyrimidines
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4
Capecitabine
Tegafur
CES
CYP2A6
FUMP
FUDP
FUTP
RNA RNA damage incorporation
CDA
5’-hydroxytegafur
FUDR
FdUMP
FdUDP
FdUTP
DNA incorporation
5’dFCR
5’dFUR
Excretion (urine)
10% >80% DPD
TYMS
dTMP
DNA synthesis
F-ß-AL
FUPA DHFU
TP
DNA damage
5-FU
-
dUMP
Figure 1. Schematic overview of fluoropyrimidine metabolism
DPYD
1-5%
Inhibition of DNA synthesis and repair
TS
In brief: tegafur, 5FU, capecitabine are metabolised into three major metabolites. FdUMP, which inhibits TS and prevents conversion of dUMP to dTMP, which is necessary for pyrimidine and DNA synthesis. FdUTP is incorporated in DNA, FdUTP is incorporated in RNA, both resulting in cell death.
Abbreviations: CES: carboxylesterase; 5’dFCR: 5’-deoxy-5-fluorocytidine; CDA: cytidine deaminase; 5’dFUR: 5’-deoxy-5-fluorouridine; TP: thymidine phosphorylase; 5-FU: 5-fluorouracil; FUMP: fluorouridine monophosphate; FUDP: fluorouridine diphosphate; FUTP: fluorouridine triphosphate; RNA: ribonucleic acid; FUDR: fluorodeoxyuridine; FdUMP: fluorodeoxyuridine monophosphate; FdUDP: fluorodeoxyuridine diphosphate; FdUTP: fluorodeoxyuridine triphosphate; DNA: deoxyribonucleic acid; TS: thymidylate synthase; TYMS: gene encoding TS; dUMP: deoxyuridine monophosphate; dTMP: deoxythymidine monophosphate; DPD: dihydropyrimidine dehydrogenase; DPYD: gene encoding DPD; DHFU: 5,6-dihydrofluorouracil; FUPA: fluoro-ß-ureidopropionate; F-ß-AL: fluoro-ß-alanine.
