Characteristics of the accumulation of methotrexate polyglutamate derivatives in Ehrlich ascites tumor cells and isolated rat hepatocytes.

  title={Characteristics of the accumulation of methotrexate polyglutamate derivatives in Ehrlich ascites tumor cells and isolated rat hepatocytes.},
  author={David W. Fry and David A. Gewirtz and Jack C. Yalowich and I. David Goldman},
  journal={Advances in experimental medicine and biology},
The intracellular synthesis and retention of polygammaglutamyl derivatives of methotrexate and their interactions with H2 folate reductase was evaluated in the Ehrlich ascites tumor cell and the isolated rat hepatocyte. Methotrexate polyglutamates were detected within 15 minutes in hepatocytes exposed to 1 microM methotrexate, and continued to accumulate for at least 60 minutes producing a large transmembrane gradient. These derivatives appeared to be preferentially retained within the cell… Expand
5 Citations
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Glutamine supplementation enhances the tumoricidal effectiveness of methotrexate while reducing its morbidity and mortality in this sarcoma rat model. Expand
Effect of glutamine on methotrexate efficacy and toxicity.
These studies suggest that GLN supplementation is safe in its administration to the tumor-bearing host receiving MTX, and may serve to increase the therapeutic window of this chemotherapeutic age. Expand
Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism.
  • B. Shane
  • Biology, Medicine
  • Vitamins and hormones
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Synthesis of methotrexate polyglutamates in L1210 murine leukemia cells.
The ability of L1210 mouse leukemia cells and of a mutant methotrexate-resistant cell line (L1210/MTX) to synthesize metotrexate polyglutamates was studied, providing evidence that these metabolites may be as potent antagonists of folate metabolism as is methot Rexate itself. Expand
The pteroylglutamate analog methotrexate (MTX) is a potent inhibitor of the enzyme dihydrofolate reductase and an important antineoplastic agent. Recently synthesis of poly-y-glutamyl metabolites ofExpand
Mechanism of action of methotrexate. IV. Free intracellular methotrexate required to suppress dihydrofolate reduction to tetrahydrofolate by Ehrlich ascites tumor cells in vitro.
The requirement for free intracellular methotrexate to abolish tetrahydrofolate synthesis appears to be the basis for the observations from this laboratory that free intrACEllular metotrexate is necessary to suppress [3H]deoxyuridine incorporation into DNA and [14C]formate incorporation into RNA, DNA, and protein. Expand
The Mechanism of Action of Methotrexate: II. Augmentation by Vincristine of Inhibition of Deoxyribonucleic Acid Synthesis by Methotrexate in Ehrlich Ascites Tumor Cells
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Methotrexate polyglutamate synthesis by cultured human breast cancer cells.
It is demonstrated that methotrexate polyglutamates are readily formed in human tumor cells and bind to dihydrofolate reductase, and these forms of the drug may be important determinants of the duration of action and, ultimately, the cytotoxicity of metHotrexate in human solid tumors. Expand
Formation of methotrexate polyglutamates in rat hepatocytes.
The present studies demonstrate another important biosynthetic capacity of the freshly isolated hepatocyte and suggest the usefulness of this system for studying the mechanism of, and controlling factors in, the synthesis of polyglutamate derivatives of MTX. Expand
Transport, binding, and polyglutamation of methotrexate in freshly isolated rat hepatocytes.
There are multiple routes for methotrexate transport in the rat hepatocyte that appear to be, at least in part, distinct from the routes for folic acid and the tetrahydrofolate cofactors. Expand
Characteristics of the vincristine-induced augmentation of methotrexate uptake in Ehrlich ascites tumor cells.
The data suggest that this effect of vincristine represents an interaction with a cellular element(s) that is different from the interaction which results in the arrest of cell division in metaphase, and that this agent enhances methotrexate uptake by the inhibition of cellular energy metabolism with the consequent inhibition of an energy-dependent process which limits metotrexate accumulation within the cell. Expand
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