title: A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate, pemetrexed.
abstract: Pemetrexed is a novel antifolate effective in the treatment of mesothelioma. Studies were undertaken to characterize the transport of this antifolate in this tumor. We report the presence of a novel, concentrative high-affinity transport activity in three human mesothelioma cell lines, characterized in detail in the NCI-H28 line, with a pemetrexed influx K(t) of 30 nM and V(max) of 10 nmol/g protein/min. This route is highly specific for pemetrexed, with a substrate specificity pattern quite different from that of the reduced folate carrier and folate receptors. In particular, there is an apparent relatively low affinity for other antifolate inhibitors of dihydrofolate-reductase (MTX, aminopterin, PT523) and thymidylate synthase (ZD1694, ZD9331). Besides its impact on the transport of pemetrexed, this high-affinity route may represent another pathway by which physiological folates are transported into human cells.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York 10461, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Rongbao
authors.initials: R
authors.lastname: Zhao
authors.forename: Shrikanta
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: I David
authors.initials: ID
authors.lastname: Goldman
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics*; D005971:Glutamates / Q000493:pharmacokinetics*; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D026901:Membrane Transport Proteins; D008654:Mesothelioma / Q000378:metabolism*; D008727:Methotrexate / Q000493:pharmacokinetics; D000068437:Pemetrexed; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018076:DNA, Complementary; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists; D005971:Glutamates; D026901:Membrane Transport Proteins; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D000068437:Pemetrexed; D006147:Guanine; D008727:Methotrexate