Uracile plays two roles during cell division:
It is a precursor of thymine (via thymidylate synthetase),
It is part of the composition of RNAs (synthesis of proteins, in particular cellular enzymes).
The study of the chemical formulae very clearly demonstrates the substitution
mechanism which occurs in cells.
The metabolism of 5-FU implies a reduction in 5-fluordeoxyuridine 5'monophosphate (FdUMP) which binds to thymidylate synthetase and blocks the methylation of uracile towards thymine.
Moreover, 5-FU is phosphorylated to triphosphate (FUTP) and incorporated instead of uracile in RNAs, thus blocking their transcription.
Either for advanced or metastatic diseases,
Or as adjuvant chemotherapy in advanced cancer after surgical excision (Dukes stage C).
In both indications, 5-FU is often associated either with folinic acid ('FUFOL' protocol) which increases the sensitivity of thymidylate synthetase to the action of 5-FU, or sometimes with Irinotecan ('FOLFIRI protocol) which is a topoisomérase I inhibitor and acts in synergy with 5-FU, or with oxaliplatin ('FOLFOX' protocol) which is a platin salt, particularly active on colic tumours.
Either after locoregional treatment in an adjuvant setting
Or after relapse.
5-FU is one of the components of protocols called FAC or FEC (association of 5-FU, adriamycin or epirubicin, cytoxan).
Head and neck or oesophageal epidermoid tumours
In association with cisplatin (and possibly radiotherapy)
Only specific toxicities (or major toxicities) are described here. Other common chemotherapy toxicities are described in the chapter on chemotherapy toxicity.
It is described as palmar plantar erythrodysesthesia or palm and sole toxicity. At the beginning it is a single erythrodermia then desquamation occurs on the palm or the sole. Treatment by a soothing ointment is often necessary.
Electrocardiogram abnormalities or even cardiac insufficiency or myocardial infarction can be observed after or during 5-FU infusion. These complications are most often observed after cardiac irradiation (for instance, when irradiating internal mammary nodes).
Dihyropyrimidine dehydrogenase deficiency (DPD)
About 5% of the population have a dihyropyrimidine dehydrogenase deficiency (rarely complete) Thus, these patients will not metabolise 5-FU and a toxicity risk (with haematological toxicity and severe diarrhoea) could be observed. For some authors, research for such deficiency should be systematic before any use of 5-FU.
There are at least two different situations:
The usual dosage is around 500 to 600 mg per m2, every 3 weeks.
A prolonged infusion of 2 to 3 g /m2 in 44 hours, with an electrical pump (allowing return home ) combined with folinic acid infusion.