title: In vitro activity of novel antifolates against human squamous carcinoma cell lines of the head and neck with inherent resistance to methotrexate.
abstract: A series of 7 human squamous carcinoma cell lines of the head and neck (HNSCC), grown in standard medium containing high folate concentrations and in "folate-conditioned" medium containing nanomolar concentrations of folates, were all found to be sensitive (IC50: less than or equal to 50 nM) in growth-inhibition studies to methotrexate (MTX) following drug exposure for 7 days. However, when MTX exposure was limited to 24 hr, only 2 out of 7 HNSCC cell lines were sensitive to MTX (IC50: less than 500 nM), 2 were moderately sensitive (IC50: 1-2 microM), and 3 exhibited inherent resistance to MTX (IC50: greater than 250 microM). In these last 3 cell lines, the mechanism of resistance was not correlated with altered membrane transport of MTX or changes in dihydrofolate reductase activity, but rather was associated with a 3-fold lower activity of intracellular folylpolyglutamate synthase (FPGS) activity compared to MTX-sensitive HNSCC cells. The 3 cell lines exhibiting inherent resistance to a short exposure to MTX, however, did not show inherent cross-resistance after exposure for 24 hr to one or more of 3 novel antifolate compounds. These compounds, which appear to be more efficiently transported and polyglutamylated than MTX, include: 10-ethyl-10-deazaaminopterin (10-EdAM), 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI-198,583), and 5,10-dideazatetrahydrofolic acid (DDATHF). These results indicate that antifolate membrane transport and intracellular FPGS activity are important factors in determining sensitivity or resistance of HNSCC cells to short-term antifolate compound exposures.
authors.affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, University Hospital Utrecht, The Netherlands.
authors.forename: B F
authors.initials: BF
authors.lastname: van der Laan
authors.forename: G
authors.initials: G
authors.lastname: Jansen
authors.forename: G A
authors.initials: GA
authors.lastname: Kathmann
authors.forename: G R
authors.initials: GR
authors.lastname: Westerhof
authors.forename: J H
authors.initials: JH
authors.lastname: Schornagel
authors.forename: G J
authors.initials: GJ
authors.lastname: Hordijk
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives / Q000494:pharmacology; D001692:Biological Transport; D002294:Carcinoma, Squamous Cell; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006258:Head and Neck Neoplasms; D006801:Humans; D008727:Methotrexate / Q000378:metabolism / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013763:Tetrahydrofolates / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C045894:lometrexol; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; C040210:edatrexate; D000630:Aminopterin; C059966:ICI 198583; D008727:Methotrexate