MULTIDRUG RESISTANCE PROTEINS OF THE ABCC SUBFAMILY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 285

11.5.8. ABCC/MRP Efflux Pumps in Human Cancers
Most of the ABCC/MRP efflux pumps have been shown in animal and in vitro studies
to confer resistance to a wide variety of anticancer and antiviral drugs (Section 11.4
and Table 11.2). Despite this established contribution to the development of cellular
drug resistance, the role of ABCC/MRP efflux pumps in clinical drug resistance is not
well defined and remains under investigation. 211 , 212 A large number of studies shows
the overexpression of one or more ABCC/MRP mRNAs in various human cancers and
in cell lines derived from human cancers. Several studies have correlated this overex-
pression with clinicopathological data. High levels of ABCC1 mRNA are, for instance,
a prognostic factor for a poor outcome of retinoblastoma 213 and neuroblastoma. 214
Fewer studies have analyzed clinical specimens with respect to ABCC/MRP protein
levels and to the immunolocalization of these efflux pumps (Table 11.3). In sev-
eral trials, focusing primarily on ABCC1, the protein levels were determined before
and after chemotherapy or were correlated with outcome. The ABCC1 protein level
appears to be a significant negative indicator of response to chemotherapy and over-
all survival in some cancers (e.g., in non-small cell lung cancer 240 , 241 and in breast
cancer). 216 , 242 , 243 Other studies have correlated the ABCC1 protein levels with cancer
stage and invasiveness of prostate cancer 244 and with stage 245 and overall survival 246
in acute myeloblastic leukemia. The determination of the ABCC/MRP protein expres-
sion profile in a given tumor sample, together with knowledge of the drug resistance
profile of each ABCC/MRP transporter as well as the detection and localization of
uptake transporters, will advance the development of personalized chemotherapy reg-
imens for patients.
11.6. DOUBLE-TRANSFECTED CELLS AS A MODEL SYSTEM TO
STUDY THE VECTORIAL TRANSPORT OF SUBSTANCES
Vectorial transport is a key step in the hepatobiliary and renal elimination of endoge-
nous substances and xenobiotics. Double-transfected cells expressing a basolateral
uptake transporter and an apical ATP-dependent efflux pump simultaneously are now
considered valuable tools for the study of this vectorial transport in vitro. 143 , 247 , 248
In addition, vectorial transport studies are of interest for pharmacokinetic analyses in
drug discovery, maximizing drug efficacy and reducing interference of the transport
of physiological endogenous substrates by drug candidates at the sites of their uptake
and elimination.
For vectorial transport studies in vitro, it is required that the cells grow in a polar-
ized fashion, forming a basolateral and an apical plasma membrane domain. This can
be achieved by culturing them on semipermeable filter supports. The human colon
carcinoma Caco-2 cell line, for instance, gains an epithelial cell polarity when cultured
on certain filter membranes, with ABCC2 being localized in the apical membrane. 249
The opossum kidney OK cells and the porcine kidney LLC-PK 1 cells are estab-
lished cell culture models of renal epithelial vectorial transport. 250 MDCK cells stably