CsA, PSC833, and quinine showed some overall survival benefit in several
anticancer drug treatments in P-gp positive patients with poor risk acute
myelogenous leukemia (AML), untreated AML, and high myelodysplastic
syndrome (MDS) respectively, but had no effect on the same anticancer drugs
on the cancer type from different trial group (Table 6.2). All these
controversial results could be partially due to the limitations of MDR
inhibitors (such as potency, low specificity, potential toxicity, and nonoptimal
PK profiles) and the inadequate clinical trial designs (Szakacs et al., 2006).
Other efflux transporters like BCRP and MRP1/2 (Borst et al., 2000; Doyle
et al., 1998) also have to be taken into account for development of drug
resistance, and new chemoagents are needed for that. Except in the oncology
area, efflux pumps have been also shown to confer resistance for the drugs
targeting to the central nervous system (such as epilepsy) (Kwan and Brodie,
2005), central infections (such as HIV) (Kwan and Brodie, 2005), and T-cells
(such as inflammation diseases) (Oerlemans et al., 2006; van der Heijden et al.,
2004a, 2004b).
Other strategies for reversing the MDR are also being considered, some of
these involve using coadministration of antisense oligonucleotides, hammer-
head ribozymes and short-interfering RNA (iRNA) to suppress P-gp
expression (Pichler et al., 2005; Xu et al., 2004); antagonism of xenobiotic
nuclear receptor SXR involved in the induction of P-gp and CYP3A4
(Forman et al., 2002; Synold et al., 2001); and bolstering the P-gp expression in
bone marrow stem cells, which are more prone than other cells to anticancer
agents’ toxicity and hence limiting their doses, by transfection with MDR1
cDNA and making these stem cells more resistant to chemoagents, thereby
allowing higher doses of the drugs to be used for longer periods of time
resulting in increased efficacy of the treatment (Gottesman et al., 1999).
Although the transcriptional repression of MDR is promising and attractive
strategy, it is still a challenging task tosafely deliver the gene regulators to the
cancer cellsin vivo(Pichler et al., 2005; Szakacs et al., 2006; Xu et al., 2004). In
contrast to normal stem cells, tumorigenic stem cells with high expression of
drug transporters can also lead to drug resistance. In chemotherapy, normal
cells are killed, but the tumor stem cells survive and proliferate, leading to
recurring tumor composed of tumor stem cells and cells of variable,
committed lineage (Dean et al., 2005). Mutations in the tumor stem cells
and their descendents can further confer drug resistance phenotype, and
resulting in tumor growth.
For some hydrophilic drug molecules, the rates of passive diffusion through
cell membrane are low and transporter-mediated uptake is the major route for
the drug getting into the target cells.In vitro cellular-based assays have
demonstrated that inefficient cellular uptake is a potential mechanism of
resistance to anticancer drugs such as the nucleoside drugs (Hoffman, 1991;
Mackey et al., 1998a), in particular: cytarabine (Wiley et al., 1982, 1985),
fludarabine (Gati et al., 1998), cladribine (Gati et al., 1998; Wright et al., 2002),
5-fluoro-2^0 -deoxyuridine (FdUrd) (Sobrero et al., 1985a, 1985b), 5-fluorouracil
TRANSPORTERS IN DRUG RESISTANCE 155