T. Abe et al., LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers, GASTROENTY, 120(7), 2001, pp. 1689-1699
(Background & Aims) under bar: One approach to the development of targeted
cancer chemotherapy exploits increased up take of the agent into neoplastic
cells. In this scenario, higher concentrations of the agent in cancer cell
s are responsible for differential killing, whereas the low concentration i
n normal human cells decreases side effects. The aim of this study was to i
solate an organic anion transporter that is weak in normal cells, but abund
antly expressed in cancer cells, to deliver the anticancer drugs to the cel
ls. (Methods) under bar: A human liver complementary DNA (cDNA) library was
screened with liver-specific transporter (LST)-1 cDNA as a probe. Northern
blot analyses were performed using the isolated cDNA (termed LST-2). An LS
T-2-specific antibody was raised. and immunohistochemical analyses includin
g immunoelectron microscopy were performed. Xenopus oocyte expression syste
m was used for functional analysis. We also established a permanent cell li
ne that consistently expresses LST-2 to examine the relationship between me
thotrexate uptake and sensitivity. (Results) under bar: The isolated cDNA,
LST-2, has 79.7% of overall homology with human LST-1, LST-2 exclusively ex
pressed in the liver under normal conditions and its immunoreactivity was h
ighest at the basolateral membrane of the hepatocytes around the central ve
in. Although its weak expression in the liver, LST-2 is abundantly expresse
d in the gastric, colon, and pancreatic cancers. On the other hand, the LST
-1 was only detected in a hepatic cell line. LST-2 transports methotrexate
in a saturable and dose-dependent manner. Furthermore, introduction of the
LST-2 gene into mammalian cells potentiates sensitivity to methotrexate, (C
onclusions) under bar: LST-2 is one of the prime candidate molecules for de
termining methotrexate sensitivity and may be a good target to deliver anti
cancer drugs to the gastrointestinal cancers.