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A wild-type Datura innoxia cell line (Px4) was used to select methotrexate-resistant cells through a stepwise procedure. Two independently selected cell lines, MTX161 and MTX132, were stable and shown to be 5 to 15 times more resistant to methotrexate than wild type. These methotrexate-resistant cells were similar to the wild-type cells in levels and kinetic properties of dihydrofolate reductase, the sensitivity of dihydrofolate reductase to methotrexate, the binding of [3H]methotrexate to soluble proteins, and the formation of methotrexate polyglutamate derivatives. High performance liquid chromatographic analyses indicated that methotrexate polyglutamylation is only slight and may not be significant in the toxicity of methotrexate to Datura cells. The uptake of methotrexate was also investigated in the wild-type and resistant cells. The Px4 cells exhibited a linear uptake that lasted for 1 to 7 h. The uptake was saturable, pH and energy dependent, and had a Km of 65.6 nM and a Vmax of 12.5 nmol h-1g-1 fresh weight. Neither MTX161 nor MTX132 exhibited the sustained uptake of methotrexate shown by the Px4 cells. As a result, there were greatly reduced concentrations of intracellular methotrexate in resistant cells. Resistant cell lines had 2- to 3-fold higher Km values for methotrexate uptake compared with Px4 cells. It is proposed that these cells became resistant as a result of a stable change in the membrane transport system for methotrexate.

Methotrexate Resistance in Datura innoxia (Uptake and Metabolism of Methotrexate in Wild-Type and Resistant Cell Lines)