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DCK is a key cytosolic enzyme in the DNA-synthesis salvage pathway and is responsible for the phosphorylation of clofarabine.

Clofarabine is phosphorylated to form clofarabine triphosphate, which competes with dATP for DNA polymerase-α and -ε. At the same time, clofarabine-monophosphate is incorporated into internal and terminal DNA sites, which impaired DNA elongation and repair. Clofarabine triphosphate inhibits ribonucleotide reductase with IC50 value of 65 nM, which then reduced dCTP and dATP. Clofarabine is efficiently transported into cells through nucleoside transporters hENT1, hENT2, and hCNT2. Clofarabine results in release of cytochrome c, apoptosis protease-activating factor 1 (APAF1), apoptotic-inducing factor (AIF) and caspase 9 into the cytosol. In both rapidly growing and quiescent tumours, clofarabine has anticancer activity because of its inhibition of DNA synthesis and induction of apoptosis.

Implanted human tumour xenografts in athymic nude or severe combined immune deficiency mice, Clofarabine administered intraperitoneally had significant antitumor activity.

References:

[1]. Bonate PL, Arthaud L, Cantrell WR Jr, et al. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat Rev Drug Discov, 2006, 5(10): 855-863.

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