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In vitro activity of novel antifolates against human squamous carcinoma cell lines of the head and neck with inherent resistance to methotrexate
Author(s) -
van der Laan B. F. A. M.,
Jansen G.,
Kathmann G. A. M.,
Westerhof G. R.,
Schornagel J. H.,
Hordijk G. J.
Publication year - 1992
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910510613
Subject(s) - antifolate , methotrexate , dihydrofolate reductase , intracellular , cell culture , epidermoid carcinoma , head and neck squamous cell carcinoma , ic50 , in vitro , chemistry , pharmacology , antimetabolite , biochemistry , biology , medicine , immunology , carcinoma , cancer , head and neck cancer , genetics
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 (IC 50 : ⩽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 (IC 50 : <500 nM), 2 were moderately sensitive (IC 50 : 1‐2 μM), and 3 exhibited inherent resistance to MTX (IC 50 : >250 μM). In these last 3 cell lines, the mechanism of resistance was not correlated with altered membrane transport of MTX or changes in dihydrofo‐late 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‐deazaami‐nopterin (10‐EdAM), 2‐desamino‐2‐methyl‐N 10 ‐propargyl‐5,8‐dideazafolic acid (ICI‐198,583), and 5, 10‐dideazatetrahydrofo‐lic 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.