Impaired polyglutamylation of methotrexate as a cause of resistance in ccrf-cem cells after short-term, high-dose treatment with this drug

Giuseppe Pizzorno, Enrico Mini, Marcella Coronnello, John J. McGuire, Barbara A. Moroson, Arlene R. Cashmore, Robert N. Dreyer, James T. Lin, Teresita Mazzei, Piero Periti, Joseph Bertino

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102 Scopus citations

Abstract

Two methotrexate-resistant sublines, CCRF-CEM R3/7 and CCRF-CEM R30/6, were selected from the human leukemia T-lymphoblast cell line, CCRF-CEM, after repeated exposures (7 and 6 times, respectively) for 24 h to constant concentrations (3 and 30 μM)of the drug. Analysis of the mechanism of resistance revealed no differences in levels of dihydrofolate reductase activity, its binding affinity for methotrexate, or in methotrexate transport between the CCRF-CEM parent and methotrexate-resistant cell lines. The development of resistance to methotrexate was associated with a marked decrease in the intracellular level of methotrexate polyglutamates. Although the resistant sublines were able to form substantial amounts of folate polyglutamates when measured with [3H]folic acid, the level of polyglutamates formed was decreased to about 50% of that formed by the parent cell line. No qualitative differences in folate polyglutamates formed were noted between the parental and resistant sublines. This is the first example of a cell line which displays resistance which is solely attributable to defective methotrexate polyglutamate synthesis.

Original languageEnglish (US)
Pages (from-to)2149-2155
Number of pages7
JournalCancer Research
Volume48
Issue number8
StatePublished - Apr 15 1988

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Pizzorno, G., Mini, E., Coronnello, M., McGuire, J. J., Moroson, B. A., Cashmore, A. R., Dreyer, R. N., Lin, J. T., Mazzei, T., Periti, P., & Bertino, J. (1988). Impaired polyglutamylation of methotrexate as a cause of resistance in ccrf-cem cells after short-term, high-dose treatment with this drug. Cancer Research, 48(8), 2149-2155.