Concentrating capacity of the human reduced folate carrier (hRFC1) in human ZR-75 breast cancer cell lines

Biochemical Pharmacology
K A SharifI D Goldman

Abstract

Human RFC1 (hRFC1) transfected in transport-deficient methotrexate MTXR(R)ZR-75-1 human breast carcinoma cells (MTX(R)ZR-75/RFC) were used to investigate the impact of hRFC1 overexpression on influx and concentrative transport of methotrexate (MTX). Eight-fold overexpression of hRFC1, as determined by northern analysis, resulted in a 4-fold increase in MTX influx accompanied by a 2.4-fold increase in the steady-state level of free drug as compared with wild-type ZR-75-1 cells when the extracellular MTX level was 0.5 microM. When extracellular MTX was increased to 10 microM, the increase in influx equaled the increase in the transmembrane chemical gradient for MTX in the transfectant relative to wild-type cells. By 50 min, approximately 16-20 and 25% of the intracellular 3H represented MTX polyglutamates by HPLC analysis at [MTX]e = 0.5 and 10 microM in wild-type and transfected cells, respectively. Overexpression of hRFC1 enhanced sensitivity to MTX in MTX(R)ZR-75-1 cells by more than 250-fold. The data indicate that overexpression of hRFC1 in human cells results in comparable increases in influx and transmembrane gradients. This is different from what was reported when mouse RFC1 was transfected into murine leukemia cells, res...Continue Reading

References

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