LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers

Citation
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
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
GASTROENTEROLOGY
ISSN journal
0016-5085 → ACNP
Volume
120
Issue
7
Year of publication
2001
Pages
1689 - 1699
Database
ISI
SICI code
0016-5085(200106)120:7<1689:LAHLOA>2.0.ZU;2-I
Abstract
(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.