Unstable methotrexate resistance in human small-cell carcinoma associated with double minute chromosomes.

@article{Curt1983UnstableMR,
  title={Unstable methotrexate resistance in human small-cell carcinoma associated with double minute chromosomes.},
  author={Gregory A. Curt and Desmond N. Carney and Kenneth H. Cowan and Jacques Jolivet and B D Bailey and James C. Drake and K S Chien Song and John D. Minna and Bruce A. Chabner},
  journal={The New England journal of medicine},
  year={1983},
  volume={308 4},
  pages={
          199-202
        }
}
Resistance to antineoplastic drugs may develop through a variety of mechanisms, including deletion of membrane-transport mechanisms, an increase in target-enzyme concentration, or a deletion of an essential drug-activating enzyme. One unique mechanism for mutation to drug resistance is amplification of the gene coding for a target protein, leading to elevated levels of the protein. In studies of cultured experimental tumor-cell lines, resistance to a variety of toxic substances, including… 

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References

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Loss and stabilization of amplified dihydrofolate reductase genes in mouse sarcoma S-180 cell lines

An unstably resistant S-180 cell line (clone) that, after 3 years of continuous growth in methotrexate, generated cells containing stably amplified dihydrofolate reductase genes, and they were retained in a stable state.

Amplified dihydrofolate reductase genes in unstably methotrexate-resistant cells are associated with double minute chromosomes.

It is reported that in mouse S-180 and L5178Y cell lines unstably amplified dihydrofolate reductase DNA sequences are associated with small, paired chromosomal elements denoted "double minute chromosomes," whereas in stably amplified cells of the same origin, the genes are related with large chromosomes.

Relationship of amplified dihydrofolate reductase genes to double minute chromosomes in unstably resistant mouse fibroblast cell lines

Murine 3T6 selected in increasing concentrations of methotrexate were unstable with respect to dihydrofolate reductase overproduction and methotrexate resistance when they are cultured in the absence

Amplified dihydrofolate reductase genes are localized to a homogeneously staining region of a single chromosome in a methotrexate-resistant Chinese hamster ovary cell line.

Methotrexate-resistant Chinese hamster ovary cells selected for high resistance by progressive increments of methotrexate in the culture medium have levels of dihydrofolate reductase that are 200 times that of sensitive cells and a corresponding increase in the number of copies of the diHydrofolATE reduct enzyme gene.

Correlation of dihydrofolate reductase elevation with gene amplification in a homogeneously staining chromosomal region in L5178Y cells

Molecular hybridization of a purified [3H]DNA probe complimentary to DHFR specific mRNA with cellular DNA and RNA indicates that DHFR coding sequences are elevated several hundred fold in both nucleic acid species in the mutant cell line.

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Large, homogeneously staining chromosome regions which lack the longitudinal differentiation ordinarily revealed by cytogenetic "banding" methods have been found in antifolate-resistant Chinese

Methotrexate-resistant Chinese hamster ovary cells contain a dihydrofolate reductase with an altered affinity for methotrexate.

This study has shown that clonal isolates of Chinese hamster ovary cells that were resistant to the cytotoxic action of methotrexate and contained a dihydrofolate reductase that was less sensitive to inhibition by the drug than wild-type enzyme.

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    Proceedings of the National Academy of Sciences of the United States of America
  • 1981
Friend leukemia cells resistant to cadmium toxicity were selected and revealed that the resistant cells are nearly tetraploid and contain, on the average, three very small chromosomes that are absent from non-resistant Friend cells.

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A lymphoblastic leukemia cell line that is over 100,000-fold resistant to methotrexate (MTX) has been developed and the most striking consistent difference between the resistant and sensitive cells was the presence of a large, faintly banded region of intermediate staining intensity, termed a “homogeneously staining region” (HSR).