Resistance to Drugs Associated With the Multidrug Resistance Phenotype Following Selection With High-Concentration Methotrexate

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Abstract
To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 102- to >105-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications. [J Natl Cancer Inst 81:1250–1254, 1989]

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