Corpus ID: 10617851

Efflux of methotrexate and its polyglutamate derivatives from hepatic cells in vitro.

@article{Baliska1981EffluxOM,
  title={Efflux of methotrexate and its polyglutamate derivatives from hepatic cells in vitro.},
  author={M. Balińska and J. Galivan and J. Coward},
  journal={Cancer research},
  year={1981},
  volume={41 7},
  pages={
          2751-6
        }
}
Abstract The efflux of methotrexate and methotrexate polyglutamates was examined with primary monolayer cultures of rat hepatocytes and also with monolayer cultures of a stable hepatocarcinoma cell line (H35 cells). In this study, the polyglutamates were considered as those species with two or more additional glutamate residues. When methotrexate polyglutamates were present in hepatocytes in excess of methotrexate, efflux led to a further increase in the intracellular proportion of… Expand
Studies of formation and efflux of methotrexate polyglutamates with cultured hepatic cells.
TLDR
These results, together with those of an earlier study, suggest that the polyglutamate derivatives are forms of methotrexate which are as cytotoxic as metHotrexate but which offer a potentially greater capacity for cellular destruction because they are retained longer in the tissue. Expand
Factors controlling the concentrations of methotrexate in cultured hepatic cells.
TLDR
The polyglutamate metabolites of methotrexate are as inhibitory to the target enzyme dihydrofolate reductase as is metotrexate and have a longer half-life within the cells and thus a greater potential for cytotoxicity. Expand
Analysis of the role of membrane transport and polyglutamation of methotrexate in gut and the Ehrlich tumor in vivo as factors in drug sensitivity and selectivity.
TLDR
The data suggest that the toxic effects of methotrexate on intestinal cells may be related primarily to the action of the monoglutamate, while toxic effects on tumor cells are related to the buildup and persistence of the polyglutamate forms. Expand
Augmentation of the intracellular levels of polyglutamyl derivatives of methotrexate by vincristine and probenecid in Ehrlich ascites tumor cells.
TLDR
It is indicated that vincristine and probenecid may be potentially useful for selectively increasing methotrexate polyglutamates in tumor cells and another basis for synergism observed between alkaloids and methotreysate is introduced. Expand
Glutamylation of methotrexate in hepatoma cells in vitro: regulation and the development of specific inhibitors.
TLDR
The 4-fluoroglutamyl analogs of methotrexate are effective inhibitors of dihydrofolate reductase but cannot be glutamylated, and will be utilized to probe the role of glutAMylation in antifolate activity and folate metabolism. Expand
Characteristics of methotrexate polyglutamate formation in cultured hepatic cells.
TLDR
Examination of MTX polyglutamate formation following a 24-h incubation showed concentration dependence with respect to intra- and extracellular MTX. Expand
Regulatory aspects of the glutamylation of methotrexate in cultured hepatoma cells.
TLDR
Data are presented suggesting that methotrexate polyglutamates can regulate their own synthesis, and showing that folates can modify the rates of metotrexatePolyglutamate formation, in H35 hepatoma cells in vitro. Expand
Synthesis, retention, and biological activity of methotrexate polyglutamates in cultured human breast cancer cells.
TLDR
It is demonstrated that polyglutamate formation allows a prolonged retention of drug in a noneffluxable form and prolonged inhibition of both thymidylate synthesis and cell growth following removal of extracellular drug. Expand
The kinetics of methotrexate polyglutamate formation and efflux in a human breast cancer cell line (MDA.MB.436): the effect of insulin.
TLDR
The data suggest that the ability of insulin to potentiate the cytotoxic effects of MTX may be related to the hormone's ability to modulate the synthesis ofMTX polyglutamates. Expand
In vitro formation of polyglutamyl derivatives of methotrexate and 7-hydroxymethotrexate in human lymphoblastic leukemia cells.
TLDR
A potential role for 7-hydroxymethotrexate in modulating the biochemical effects of methotrexateIn vivo is suggested, as well as an important new dimension in the pharmacological action of metHotrexate. Expand
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TLDR
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
SYNTHESIS OF METHOTREXATE POLYGLUTAMATES IN CULTURED HUMAN CELLS
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
Evidence for the cytotoxic activity of polyglutamate derivatives of methotrexate.
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TLDR
Protection studies demonstrated that both thymidine and hypoxanthine are needed to prevent methotrexate toxicity, offering evidence that inhibition of cell growth is due to a depletion of reduced folate coenzymes, and results demonstrate that the polyglutamates have at least an equivalent affinity for the enzyme in the intact cell when compared to metotrexate. Expand
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TLDR
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
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TLDR
It is suggested that the metabolism of methotrexate in cultured human fibroblasts occurs according to the following steps: saturation by nonmetabolized metotrexate of a nonexchangeable pool, addition of γ-glutamyl residues to methotRexate in a freely-exchangeable Pool, and appearance of metHotrexate polyglutAMates in a nonex changeable pool. Expand
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TLDR
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
Transport and metabolism of methotrexate in normal and resistant cultured rat hepatoma cells.
TLDR
The results suggest that the cells become resistant as a result of a stable change in the transport system for MTX, but the mechanism of this process is not yet understood. Expand
The effect of age in culture on the uptake and metabolism of methotrexate by primary cultures of hepatocytes.
  • J. Galivan
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TLDR
The ability of the cells to form polyglutamates does not appear to diminish with the age of the culture and the uptake of (+) 5-methyltetrahydrofolate and folate is not altered greatly with time in culture and is unaffected by azide. Expand
Tissue-specific synthesis of methotrexate polyglutamates in the rat.
TLDR
Synthesis of methotrexate polyglutamates in liver and kidney was limited to the interval immediately following metotrexate administration and appeared to occur by sequential addition of single glutamyl residues to so-called "free" intracellular methot Rexate. Expand
Differential cell permeability and the basis for selective activity of methotrexate during therapy of the L1210 leukemia.
TLDR
A far greater persistence of free MTX and a more sustained metabolic effect in L1210 cells than in small intestine is revealed, at least in part, to a more effective influx of drug in L 1210 cells at low plasma levels. Expand
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