In vitro activity of novel antifolates against human squamous carcinoma cell lines of the head and neck with inherent resistance to methotrexate

B F van der Laan, G Jansen, G A Kathmann, G R Westerhof, J H Schornagel, G J Hordijk

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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.

Original languageEnglish
Pages (from-to)909-14
Number of pages6
JournalInternational journal of cancer
Issue number6
Publication statusPublished - 30 Jul 1992


  • Aminopterin/analogs & derivatives
  • Biological Transport
  • Carcinoma, Squamous Cell
  • Cell Division/drug effects
  • Cell Line
  • Cell Membrane/metabolism
  • Drug Resistance/physiology
  • Drug Screening Assays, Antitumor
  • Folic Acid Antagonists/pharmacology
  • Folic Acid/analogs & derivatives
  • Head and Neck Neoplasms
  • Humans
  • Methotrexate/metabolism
  • Tetrahydrofolate Dehydrogenase/metabolism
  • Tetrahydrofolates/pharmacology
  • Tumor Cells, Cultured

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