title: Dipyridamole mediated enhanced antiproliferative activity of 10-ethyl-10-deazaaminopterin (10-EDAM) against human lung cancer cell lines.
abstract: 10-ethyl-10-deazaaminopterin (10-EDAM) is a rationally designed derivative of the antifolate, methotrexate (MTX). In a number of tumor models these design features have resulted in an improved spectrum of antiproliferative activity as compared with the parent compound. Using an MTT growth assay, we compared in vitro antiproliferative activity of 10-EDAM with MTX in eight lung cancer cell lines. Growth was inhibited in all lines tested by clinically achievable concentrations of 10-EDAM (0.1-1,000 nM). 10-EDAM was more cytotoxic than MTX at the same concentrations in all eight lung cancer cell lines. In an effort to enhance the antiproliferative effect, we evaluated the addition of dipyridamole (DPM), an inhibitor of nucleoside transport, to 10-EDAM (0.1-10 microns). DPM decreased the concentration of 10-EDAM required to cause 50% growth inhibition (IC50) in all eight cell lines tested. This suppression was statistically significant by 2-sided sign test (P = .0078). By contrast, the IC50 of MTX was decreased in only two of the eight cell lines when DPM was added (0.1-10 microM). In defined thymidine depleted media, cell kill by the combination of 10-EDAM and DPM was no greater than 10-EDAM alone, consistent with the possibility that DPM exerts some of its effect by inhibition of extrinsic nucleoside salvage. In consideration of the published activity of 10-EDAM in lung cancer and the modest clinical toxicity of DPM based biochemical modulation, we conclude the current in vitro data provide justification for clinical evaluation of this combination in patients with lung cancer.
authors.affiliation: NCI-Navy Medical Oncology Branch, Division of Cancer Treatment, Bethesda, Maryland 20889, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Dearing
authors.forename: M J
authors.initials: MJ
authors.lastname: Englee-Miller
authors.forename: R A
authors.initials: RA
authors.lastname: Kratzke
authors.forename: B S
authors.initials: BS
authors.lastname: Kramer
authors.forename: E
authors.initials: E
authors.lastname: Chu
authors.forename: J
authors.initials: J
authors.lastname: Weinstein
authors.forename: M
authors.initials: M
authors.lastname: Anderson
authors.forename: D
authors.initials: D
authors.lastname: Venzon
authors.forename: J L
authors.initials: JL
authors.lastname: Mulshine
authors.forename: A F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008727:Methotrexate / Q000494:pharmacology; D009705:Nucleosides / Q000378:metabolism; D013936:Thymidine / Q000172:deficiency / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D005493:Folic Acid Antagonists; D006131:Growth Inhibitors; D009705:Nucleosides; D004176:Dipyridamole; C040210:edatrexate; D000630:Aminopterin; D013936:Thymidine; D008727:Methotrexate