Methotrexate inhibition of CCRF-CEM cultures of human lymphoblasts.

@article{Roberts1975MethotrexateIO,
  title={Methotrexate inhibition of CCRF-CEM cultures of human lymphoblasts.},
  author={D. Roberts and E. V. Warmath},
  journal={European journal of cancer},
  year={1975},
  volume={11 11},
  pages={
          771-82
        }
}
Abstract The biochemical basis for methotrexate (MTX) inhibition of human lymphoblasts was examined with the CCRF-CEM cell line. Methotrexate inhibition of growth by cultures of this human lymphoblast cell line was prevented by a combination of hypoxanthine, thymidine and deoxycytidine and was reversed competitively by folinic acid. Within 5 min MTX inhibited the incorporation of isotopically-labeled deoxyuridine, hypoxanthine and glycine into DNA, although thymidine incorporation continued… Expand
Evaluation of ribonucleoside and deoxyribonucleoside triphosphate pools in cultured leukemia cells during exposure to methotrexate or methotrexate plus thymidine.
TLDR
M mammalian cells were capable of responding in a differential fashion to pharmacological perturbations, and this capacity may play a role in determining therapeutic selectivity. Expand
Dose-related effects of methotrexate on purine and pyrimidine nucleotides and on cell-kinetic parameters in MOLT-4 malignant human T-lymphoblasts.
TLDR
These data show a close dose- and time-dependent correlation of the effects of MTX on purine de novo synthesis, UMP levels and other (deoxy)ribonucleotide pools, and on RNA and DNA synthesis in MOLT-4 cells having an active purineDeNovo synthesis. Expand
Rescue of Human Lymphoid Cells from the Effects of Methotrexate in Wfro 1
In protection experiments (5-formyltetrahydrofolate or 5-methyltetrahydrofolate added to cultures in vitro at the same time as methotrexate), 5-methyltetrahydrofolate af forded the same degree ofExpand
Methotrexate cytotoxicity in cultured human leukemic cells studied by flow cytometry.
TLDR
The finding suggest that MTX cytotoxicity is associated with inhibition of DNA synthesis resulting from the disturbance of both thymidylate and purine biosynthesis. Expand
Resistance to methotrexate in thymidylate synthetase-deficient mutants of cultured mouse mammary tumor FM3A cells.
TLDR
Results show directly that thymidylate synthetase is essential in determining the cytotoxicity of MTX by modulating the intracellular tetrahydrofolate pool. Expand
Purine modulation of methotrexate cytotoxicity in mammalian cell lines.
TLDR
The reduction of low-concentration MTX cytotoxicity by purines was associated with the reversal ofMTX-induced changes in deoxyribonucleotide pools and potentiation of MTX toxicity by purine wasassociated with substantial increases in de oxygenadenosine 5'-triphosphate levels in conjunction with low deoxythymidine 5-triph phosphate levels. Expand
Purine de novo synthesis as the basis of synergism of methotrexate and 6-mercaptopurine in human malignant lymphoblasts of different lineages.
TLDR
The data demonstrate the important role of both the activities of the PDNS and the purine salvage pathway in malignant lymphoblasts of different subclasses with respect to the synergism of MTX and 6MP. Expand
Thymidine and hypoxanthine requirements of normal and malignant human cells for protection against methotrexate cytotoxicity.
TLDR
The thymidine and Hyp requirements for protection of normal human granulocyte-macrophage colony-forming units, B-, and T-cells against methotrexate-induced inhibition of proliferation were compared to requirements of three malignant solid-tumor cell lines recently established from human tumor xenografts and of the CCRF-CEM T-cell leukemia to provide an explanation for why dThd alone is sufficient to protect patients against myelosuppression. Expand
Effects of methotrexate on purine and pyrimidine metabolism and cell-kinetic parameters in human malignant lymphoblasts of different lineages.
TLDR
Perturbations of ribonucleotide pools suggested an inhibition of RNA synthesis in all cell lines, indicating a balanced growth pattern in KM-3 cells and MOLT-4 cells. Expand
Misincorporation of deoxyuridine in human cells: consequences of antifolate exposure.
TLDR
Preliminary findings suggest that newly replicated DNA containing misincorporation of [3H]dU as dUMP is rapidly degraded in vivo by extensive excision-repair processes. Expand
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References

SHOWING 1-10 OF 39 REFERENCES
On the poor correlation between the inhibition by methotrexate of dihydrofolate reductase and of deoxynucleoside incorporation into DNA.
Inhibition by Methotrexate of dihydrofolate reductase and of the incorporation of deoxynucleosides into DNA has been examined in three mouse ascites cell leukemias which had differences in uptake andExpand
Elevation of thymidylate synthetase activity in CCRF-CEM cells.
TLDR
The elevation of thymidylate synthetase activity by methotrexate, deoxyuridine, thymidine, and folinic acid was attributed to a stabilization of thyridine kinase by the formation of enzyme complexes. Expand
Dihydrofolate reductase activity and deoxynucleoside incorporation into DNA of human leukocytes. Relation to methotrexate administration
TLDR
The administration of methotrexate inhibits the “drug‐induced” elevation of enzyme activity in normal leukocytes and in chronic myelogenous leukemia and the incorporation of deoxyuridine and thymidine into DNA was inhibited by metotrexate in childhood leukemia. Expand
The Mechanism of Action of Methotrexate: I. Interaction with a Low-Affinity Intracellular Site Required for Maximum Inhibition of Deoxyribonucleic Acid Synthesis in L-Cell Mouse Fibroblasts
L-cell mouse fibroblasts were loaded with methotrexate (MTX) in vitro to a level which exceeded the capacity of high-affinity intracellular binding sites, following which MTX in excess of the tightlyExpand
Studies relating to the mode of action of methotrexate. 3. Inhibition of thymidylate synthetase in tissue culture cells and in cell-free systems.
TLDR
The results are consistent with the interpretation that inside the living cell methotrexate can inhibit thymidylate synthetase directly. Expand
The intracellular concentration dependence of antifolate inhibition of DNA synthesis in L1210 leukemia cells.
TLDR
The discrepancy observed in vitro on the dose dependence of drug-related effects on DNA synthesis, namely the requirement for high levels of free MTX well in excess of that required to completely inhibit dihydrofolate reductase, most probably reflects an aberrant metabolic state under conditions that do not allow normal proliferative activity. Expand
Coordinated changes in biochemical patterns: the effect of cytosine arabinoside and methotrexate on leukocytes from patients with acute granulocytic leukemia.
Summary Cytosine arabinoside and Methotrexate alter in different ways the metabolic patterns of leukocytes from patients with acute granulocytic leukemia. The variations in the incorporation into DNAExpand
Enzyme activities and deoxynucleoside utilization of leukemic leukocytes in relation to drug therapy and resistance.
TLDR
Based on the correlations between percent of blast cells, leukocyte count, level of enzyme activity, and the activity of deoxyuridine and thymidine incorporation into DNA, blast cells from patients with acute lymphocytic leukemia appear to be more homogeneous than blast cells with acute granulocytic cancer or immature cell types of chronic granulcytic leukemia. Expand
Studies on unbalanced growth in tissue culture. I. Induction and consequences of thymidine deficiency.
Summary Thymidine-deficient growth of HeLa cells induced by either of two agents, amethopterin or 5-fluorouracil-2′-deoxyriboside, resulted in an unbalanced growth syndrome strikingly similar to thatExpand
Interaction of thymidylate synthetase and dihydrofolate reductase enzymes in vitro and in vivo.
TLDR
Methotrexate may increase thymidylate synthetase activity in cells possessing relatively large amounts of dihydrofolate reductase and small amounts of thymIDylate Synthetase, thus increasing the activity of thylaknotase in the presence of methotrexate. Expand
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