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

Background & Aims: One approach to the development of targeted cancer chemotherapy exploits increased uptake of the agent into neoplastic cells. In this scenario, higher concentrations of the agent in cancer cells are responsible for differential killing, whereas the low concentration in normal...

Full description

Saved in:

Bibliographic Details
Published in:	Gastroenterology (New York, N.Y. 1943) Vol. 120; no. 7; pp. 1689 - 1699
Main Authors:	Abe, Takaaki, Unno, Michiaki, Onogawa, Tohru, Tokui, Taro, Kondo, Tohru Noriko, Nakagomi, Rie, Adachi, Hisanobu, Fujiwara, Koh, Okabe, Mitsunori, Suzuki, Takehiro, Nunoki, Kazuo, Sato, Eiichi, Kakyo, Masayuki, Nishio, Toshiyuki, Sugita, Junichi, Asano, Naoki, Tanemoto, Masayuki, Seki, Makoto, Date, Fumiko, Ono, Katsuhiko, Kondo, Yoshiaki, Shiiba, Kenichi, Suzuki, Masanori, Ohtani, Haruo, Shimosegawa, Tooru, Iinuma, Kazuie, Nagura, Hiroshi, Ito, Sadayoshi, Matsuno, Seiki
Format:	Journal Article Conference Proceeding
Language:	English
Published:	New York, NY Elsevier Inc 01-06-2001 Elsevier
Subjects:	Amino Acid Sequence Animals Anion Transport Proteins Antimetabolites, Antineoplastic - therapeutic use Antineoplastic agents Biological and medical sciences Carrier Proteins - analysis Carrier Proteins - isolation & purification Carrier Proteins - physiology Chemotherapy Gastrointestinal Neoplasms - chemistry Gastrointestinal Neoplasms - drug therapy Humans Immunohistochemistry Liver - chemistry Medical sciences Methotrexate - pharmacokinetics Methotrexate - therapeutic use Molecular Sequence Data Pharmacology. Drug treatments Xenopus laevis MTX Km PG RFC-1 cDNA mRNA cRNA LST oatp BSP Antineoplastic agent Human Liver Pharmacology Malignant tumor Gastrointestinal Conveyor Organic anion Chemotherapy Sensitivity Specificity Digestive diseases Intestinal disease Methotrexate Gastric disease
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Background & Aims: One approach to the development of targeted cancer chemotherapy exploits increased uptake of the agent into neoplastic cells. In this scenario, higher concentrations of the agent in cancer cells are responsible for differential killing, whereas the low concentration in normal human cells decreases side effects. The aim of this study was to isolate an organic anion transporter that is weak in normal cells, but abundantly expressed in cancer cells, to deliver the anticancer drugs to the cells. Methods: 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 LST-2-specific antibody was raised, and immunohistochemical analyses including immunoelectron microscopy were performed. Xenopus oocyte expression system was used for functional analysis. We also established a permanent cell line that consistently expresses LST-2 to examine the relationship between methotrexate uptake and sensitivity. Results: The isolated cDNA, LST-2, has 79.7% of overall homology with human LST-1. LST-2 exclusively expressed in the liver under normal conditions and its immunoreactivity was highest at the basolateral membrane of the hepatocytes around the central vein. Although its weak expression in the liver, LST-2 is abundantly expressed 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 dosedependent manner. Furthermore, introduction of the LST-2 gene into mammalian cells potentiates sensitivity to methotrexate. Conclusions: LST-2 is one of the prime candidate molecules for determining methotrexate sensitivity and may be a good target to deliver anticancer drugs to the gastrointestinal cancers.
ISSN:	0016-5085 1528-0012
DOI:	10.1053/gast.2001.24804