(Grem, 1992), gemcitabine (Mackey et al., 1998b), 6-mercaptopurine (Fotoohi
et al., 2006), and 6-thiolguanine (Fotoohi et al., 2006). The NT-deficient
murine T-cell lymphoma cells AE1 (Cohen et al., 1979) exhibit greatly reduced
uptake of physiological nucleosides and high level resistance to cytotoxic
nucleosides (Cohen et al., 1979). In FdUrd-resistant human HCT-8 colon
cancer cells, there was no measurable uptake of FdUrd and no detectable ENT
functions, resulting in 700-fold resistance to the cytotoxicity of FdUrd
compared to naı ̈ve HCT-8 cell (Mackey et al., 1998b). However, the role of
uptake transporter deficiency in clinical drug resistance is less clear partially
due to the difficulties of performing transport studies on the malignant cells
derived from clinical specimens and of quantifying transporter abundance in
malignant clone mixed with normal cells. The efficiency of cytarabine uptake
by leukemic blast cells has been related to clinical outcome in AML and ALL
patients who received a standard dose of cytarabine (100–200 mg/m^2 /day). The
sensitivity to cytarabine therapy was highly correlated to nucleoside
transporter content and a deficiency in NT may impart resistance to cytarabine
(Wiley et al., 1982; Wright et al., 2002).
6.4 Polymorphism of Transporters and Interindividual Variation
It has been estimated that genetics can account for 20–95% of variability in
drug disposition and pharmacological effects although many other factors,
such as age, organ function, concomitant therapy, drug-drug interactions, and
the nature of disease, influence drug response (Kerb, 2006). Polymorphic
genetic variations have been reported in human MDR1 (P-gp), MRP1, MRP2,
BCRP, OATP (OATP1B1, OATP1B3, and OATP2B1), OAT1, OCT1, and
OCT2 (Beketic-Oreskovic et al., 1995; Ho and Kim, 2005; Kerb, 2006
Sparreboom et al., 2003). Generally, the role of single nucleotide polymorph-
isms (SNPs) in drug disposition is confirmedin vitroby measuring the efflux or
uptake activities of specific substrates in the cells or membranes expressing
recombinant protein, andin vivoby measuring the expression of mRNA or
protein in tissue samples, by assessing the intracellular accumulation of
substrates, by evaluating the pharmacokinetic alterations of drug substrates, or
by associating clinical outcome from drug substrates (Kerb, 2006).
Till date, genetic polymorphisms of human MDR1 has been extensively
investigated. There are 29 SNPs and 13 of major haplotypes of MDR1 that
have been identified. A lot of attentions have been focused on the silent
mutation (not associated with any amino acid change) C3435T in exon 26 and
nonsynonymous variants, G2677T (Ala893Ser) and G2677A (Ala893Thr). The
SNPs of MDR1 was demonstrated to be associated to the changes in P-gp
expression and function, and subsequent alteration in drug disposition.
However, much of the clinical data has been contradictory or inconclusive
(Sparreboom et al., 2003). The interindividual expression of P-gp varies
POLYMORPHISM OF TRANSPORTERS 157