A Comparison of the Transportability, and Its Role in Cytotoxicity, of Clofarabine, Cladribine, and Fludarabine by Recombinant Human Nucleoside Transporters Produced in Three Model Expression Systems

Mechanisms of anti-cancer action and pharmacology of clofarabine

“…The 8 importance of membrane nucleoside transporters in clofarabine metabolism is indicated by the fact that the rate of clofarabine uptake is ~10-fold higher by transport-competent than transport-deficient human leukemia cells [16]. In particular, cells expressing hCNT3 exhibit the highest rate of clofarabine uptake compared to the cells expressing hCNT2, hENT1, and hENT2, whereas transportdeficient and hCNT1-expressing cells demonstrate no uptake, consistent with the fact that hCNT1 is specific for pyrimidines.…”

“…Clofarabine is believed to enter cells by both facilitated and active nucleoside transport mechanisms as well as, at higher concentrations and upon longer exposure, by passive diffusion across lipid membranes [16]. The 8 importance of membrane nucleoside transporters in clofarabine metabolism is indicated by the fact that the rate of clofarabine uptake is ~10-fold higher by transport-competent than transport-deficient human leukemia cells [16].…”

Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides

“…Nearly 30% of the radioactivity associated with [ 3 H]claladribine goes through the monolayer in WT cells and the rate of transport is the same in both directions. Uptake of both cladribine and clofarabine into cells is known to be mediated mainly by the equilibrative nucleoside transporter ENT1 and the concentrative nucleoside transporter CNT3 and to a lesser extent also by ENT2 and CNT2 (41,42). Diffusion through the membrane is probably minimal, as transport of [ 3 H]cladribine through the monolayer was inhibited >90% by excess cold clofarabine (results not shown).…”

Human Biodistribution and Radiation Dosimetry of 18F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway

“…Clofarabine is transported into cells primarily via human concentrated nucleoside transporters; however, human equilibrative nucleoside transporters play a role as well (1,2). On entry into the cell, clofarabine is phosphorylated by deoxycytidine kinase (dCK), monophosphate kinase, and diphosphate kinase into its active triphosphate form (1).…”