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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

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

T Abe1, M Unno, T Onogawa

  • 1Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University School of Medicine, Sendai, Japan. takaabe@mail.cc.tohoku.ac.jp

Gastroenterology
|May 29, 2001
PubMed
Abstract

Insights

Researchers identified LST-2, a transporter highly expressed in gastrointestinal cancers but not normal liver cells. This transporter facilitates methotrexate uptake, enhancing cancer cell sensitivity and offering a new target for chemotherapy delivery.

Area of Science:

  • Molecular biology
  • Cancer research
  • Pharmacology

Background:

  • Targeted cancer chemotherapy aims to increase drug concentration in cancer cells while minimizing effects on normal cells.
  • Identifying transporters with differential expression between cancer and normal cells is crucial for targeted drug delivery.

Purpose of the Study:

  • To isolate an organic anion transporter (LST-2) that is weakly expressed in normal cells but abundant in cancer cells.
  • To evaluate LST-2's potential as a target for delivering anticancer drugs, specifically methotrexate, to gastrointestinal cancers.

Main Methods:

  • Screening a human liver cDNA library using LST-1 cDNA as a probe to isolate LST-2.
  • Northern blot and immunohistochemical analyses to determine LST-2 expression patterns.
  • Xenopus oocyte expression system for functional analysis of methotrexate transport.
  • Establishing a cell line expressing LST-2 to study methotrexate uptake and sensitivity.

Main Results:

  • LST-2 shares high homology with LST-1 but is exclusively expressed in normal liver, primarily at the basolateral membrane.
  • LST-2 is abundantly expressed in gastric, colon, and pancreatic cancers, unlike LST-1.
  • LST-2 mediates saturable, dose-dependent methotrexate transport.
  • LST-2 gene introduction enhances mammalian cell sensitivity to methotrexate.

Conclusions:

  • LST-2 is a promising candidate for determining methotrexate sensitivity in cancer cells.
  • LST-2 represents a viable molecular target for enhancing the delivery of anticancer drugs to gastrointestinal cancers.

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