Flurouracil 5FU

This widely prescribed example is active in:

♦ Breast cancer

♦ Most gastrointestinal cancers

♦ Head and neck tumours

♦ Ovarian cancer

It is metabolized to FdUMP that forms, in the presence of CH2-FH4, a stable complex inhibiting TS. It also inhibits RNA synthesis and pre-ribosomal RNA processing.

Pharmacology

Oral absorption is erratic so 5-FU is given IV both as a bolus and a prolonged infusion. It has a short initial half-life, with significant hepatic, renal, and lung clearance. Active metabolites (e.g. 5dUMP and FUTP) have variable pharmacokinetics.

Toxicities of 5-FU include myelosuppression and, particularly with 5-day schedules, stomatitis and diarrhoea. Prolonged infusion overcomes the initial rapid clearance, resulting in differing toxicities with minimal bone marrow effects. Instead, cutaneous toxicity known as hand-foot syndrome occurs. Neurotoxicity and cardiotoxicity may also occur. Resistance to 5-FU therapy can be due to:

♦ Altered transport

♦ Folate depletion

♦ Changes in TS expression (due to gene amplification or post-transcriptional factors)

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