Corpus ID: 8813064

The effect of methotrexate on intracellular folate pools in human MCF-7 breast cancer cells. Evidence for direct inhibition of purine synthesis.

  title={The effect of methotrexate on intracellular folate pools in human MCF-7 breast cancer cells. Evidence for direct inhibition of purine synthesis.},
  author={C. Allegra and R. Fine and J. Drake and B. Chabner},
  journal={The Journal of biological chemistry},
  volume={261 14},
This report details the effects of methotrexate on the intracellular folate pools of the MCF-7 human breast cancer cell line. To achieve this goal, we designed a high-pressure liquid chromatography system capable of separating the physiologic folates. The folate pools were quantitated following growth and equilibration in 2.25 microM radiolabeled folic acid. Each of the intracellular folates was identified by coelution with standard folates and by chemical/biochemical tests unique to each of… Expand
Relationship of reduced folate changes to inhibition of DNA synthesis induced by methotrexate in L1210 cells in vivo.
Reduced folate levels and DNA synthesis were examined in L1210 cells in mice after exposure to a wide range of methotrexate doses and sustained inhibition of DNA synthesis was generally associated with maintenance of an expanded FH2 pool and delay in repletion of the combined tetrahydrofolate pools. Expand
Role of methylenetetrahydrofolate depletion in methotrexate-mediated intracellular thymidylate synthesis inhibition in cultured L1210 cells.
The effect of low methotrexate levels on methylenetetrahydrofolate and four other reduced folate pools in cultured L1210 cells has been examined over a 48-h period and the ratio of dihydro folate to total reduced folates was quantitatively most consistent with thymidylate synthesis and growth inhibition results. Expand
( MCF-7 ) during Leucovorin Rescue in a Human Breast Cancer Cell Line Interaction of Methotrexate Polyglutamates and Dihydrofolate Updated
Previous investigations have suggested that high-dose methotrexate with leucovorin rescue is a potentially useful strategy for overcoming antifolate resistance. Interactions between methotrexateExpand
Mechanism of leucovorin reversal of methotrexate cytotoxicity in human MCF-7 breast cancer cells.
The ability of leucovorin and its metabolites to compete with direct inhibitors of dihydrofolate reductase and other metabolically important folate-dependent enzymes appears to be associated with leucovsky rescue in this intact cell system. Expand
Intracellular metabolism of 5-formyl tetrahydrofolate in human breast and colon cell lines.
It is suggested that prolonged exposure to even relatively low doses of 5-formyltetrahydrofolate may be optimal for intracellular metabolism to the most biologically relevant forms for ternary complex formation with thymidylate synthase and fluorodeoxyuradylate, since longer exposures result in a greater accumulation of the higher polyglutamates. Expand
Further studies on the pharmacologic effects of the 7-hydroxy catabolite of methotrexate in the L1210 murine leukemia cell.
Very weak inhibition of L1210 leukemia cell growth and purine, pyrimidine and tetrahydrofolate synthesis by the polyglutamyl congeners of 7-OH-MTX is demonstrated. Expand
Methotrexate alters carbon flow through the hepatic folate-dependent one-carbon pool in rats.
The tracer kinetic experiments quantitatively demonstrate the extent to which methotrexate alters the actual carbon flow through the hepatic folate-dependent one-carbon pool, primarily directed at diminishing the reductive carbon flow towards methyltetrahydrofolate and methionine synthesis. Expand
Interaction of methotrexate polyglutamates and dihydrofolate during leucovorin rescue in a human breast cancer cell line (MCF-7).
These studies provide direct evidence that competition during leucovorin rescue occurs at the level of dihydrofolate reductase between methotrexate polyglutamates and di hydrofolates in intact human cells. Expand
The characteristics and consequences of folate depletion in hepatoma cells in vitro by inhibition of dihydrofolate reductase.
The reduction in cellular folates caused by growth in nM folic acid caused enhanced growth inhibitory activity of several antifolates and the enhanced sensitivity to PDDF and DDATHF may be analogous to the reason for their synergism with the low concentration of metoprine. Expand
Modulation of the cytotoxicity of 3'-azido-3'-deoxythymidine and methotrexate after transduction of folate receptor cDNA into human cervical carcinoma: identification of a correlation between folate receptor expression and thymidine kinase activity.
The direct correlation of FR expression and TK activity indicates a previously unrecognized consequence of FR overexpression and conferred significant biological properties to sense cells as demonstrated by augmented phosphorylation of 3'-azido-3'-deoxythymidine (AZT) and concomitantly greater sensitivity to the cytotoxic effects of AZT. Expand


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