Difluorodeoxycytidine gemcitabine

This fluorinated analogue has better membrane permeation and affinity for deoxycytidine kinase than Ara-C. Intracellular retention is prolonged, partly due to a unique self-potentiation in which the bi-and tri-phosphates facilitate the phosphorylation of the parent compound, as well as inhibiting its catabolism.

Active metabolite dF-CTP is incorporated into DNA, followed only by one more normal nucleotide, resulting in protection of the DNA from repair enzymes ('masked termination'). It is probably the saturable formation of dF-CTP that contributes to the clinical schedule dependency of gemcitabine, usually given IV, weekly for 3 weeks out of 4. Toxicities include:

♦ Flu-like symptoms

♦ Transaminitis

♦ Peripheral oedema

♦ Myelosuppression

♦ Possible nephrotoxicity

There is some evidence for synergy with cisplatin, the extent of which appears to be schedule-dependent. It is active in pancreatic cancer (where there is improved symptom control in comparison with single-agent 5-FU) as well as in lung, breast, and bladder cancer.

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