Up-Regulated Transport of Methotrexate and 5-Methyltetrahydrofolate in a Human Breast Cancer Cell Line
In a majority of tumor cells, a high affinity/low capacity transport system mediates the uptake of 5-substituted reduced folates and the analog methotrexate (MTX),1–3 an important chemotherapeutic agent. The relatively low levels of the MTX carrier prompted studies on selecting variants able to up-regulate this system. Such strategy was first introduced by Sirotriak4, who by cultivating L1210 cells in progressively decreasing and growth limiting concentrations of (6R,S)-5-formyltetrahydrofolate (5-HCO-H4PteGlu), selected cells with increased transport capacities for this compound. A similar approach was used to obtain a variant of human erythroleukemia line that exhibited elevated influx.Vmax for MTX and 5-HCO-H4PteGlu relative to the parental cells5. Up-regulation of the reduced folate carrier was also found in human CCRF-CEM leukemia cells adapted to grow on < 1 nM 5-HCO-H4PteGIu,t6 whereas cultivation in the presence of low concentrations of folate induced an increased level of a membrane-associated folate-binding protein7,8.
KeywordsLeukemia MgCl Barium Methotrexate Folate
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