NUCLEOSIDE TRANSPORTERS: CNTs AND ENTs - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 188

its pharmacokinetic and toxicological properties. Finally, nucleoside transporters are
potential drug targets. By modulating extracellular concentrations of adenosine, nu-
cleoside transport inhibitors can regulate a variety of physiological processes, which
can potentially lead to therapeutic benefits.
Nucleoside analogs are an important class of drugs used in the treatment of var-
ious forms of leukemia (e.g., cytarabine, fludarabine, cladribine) as well as in solid
tumors (e.g., gemcitabine). All of the anticancer nucleoside analogs share a similar
mechanism of action. After entering the cells, nucleoside analogs undergo sequential
phosphorylation to form the corresponding nucleoside triphosphates, which exert cy-
totoxicity by interfering with DNA and/or RNA synthesis and metabolisms. 5 Many
anticancer nucleoside analogs are hydrophilic and rely on nucleoside transporters, es-
pecially ENT1, to enter cells. In this case the number of functional transporters on the
target cells becomes an important determinant for intracellular drug bioavailability
and, consequently, responsiveness to therapy. Down-regulation of transporter expres-
sion or selection of transporter-deficient cells may contribute to clinical resistance to
cytotoxic nucleoside analogs. 129 Indeed, many in vitro studies have demonstrated that
nucleoside transporters are necessary for many nucleoside analogs to enter cells, and
deficiency in transport can result in resistance to cytotoxic nucleoside analogs such
as cytarabine, 5-fluorouridine, 5-fluorodeoxyuridine, and gemcitabine. 24 , 26 , 44 , 129 For
example, Mackey et al. have shown in a panel of cancer cell lines that treatment of
cells with ENT inhibitors such as NBMPR or dipyridamole increases resistance to
gemcitabine 39- to 1800-fold. 24 Consistent with the in vitro observations, several
recent clinical studies have implicated a role of hENT1 in clinical resistance to cancer
chemotherapy. Galmarini et al. retrospectively analyzed the effects of hENT1 mRNA
expression on efficacy of cytarabine treatment of acute myelogenous leukemia in
blast cells of 123 patients treated with cytarabine. Decreased expression of hENT1
was associated with an increased risk of early relapse. 130 Stam et al. studied 18 in-
fants and 24 children with acute lymphoblastic leukemia to determine why infants
were sensitive to cytarabine. Their results showed that leukemic blasts from infants
were threefold more sensitive to cytarabine than blasts from children. 131 Decreased
mRNA levels of deoxycytidine kinase (dCK) but increased levels of hENT1 were
observed in infants, which was thought to be responsible for the increased sensitiv-
ity of infant acute lymphocytic leukemia. In the case of gemcitabine, Spratlin et al.
first examined hENT1 and hCNT3 expression in tumor biopsies from 21 pancre-
atic cancer patients treated with gemcitabine. Their analysis indicated that patients
with detectable hENT1 immunostaining had a significantly longer survival time af-
ter gemcitabine chemotherapy than did patients without detectable hENT1. 132 More
recently, Giovannetti et al. characterized the expression pattern of genes involved in
gemcitabine activity in pancreas tumor specimens from 102 gemcitabine-treated pa-
tients and its correlation with treatment outcome. 133 hENT1 expression significantly
correlated with clinical outcome; patients with high levels of hENT1 had a signifi-
cantly longer overall survival. 133 These encouraging results suggest that measurement
of transporter abundance may provide a predictive tool for guiding the appropriate
use of anticancer drugs in individual patients for treatment optimization.
Nucleoside transporters are found in absorptive and excretory organs and thus
may influence the systemic pharmacokinetics of nucleoside analogs. For example, in