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

  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},
  volume={308 4},
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… 

Tables from this paper

Molecular and Cytogenetic Analysis of Multidrug Resistance-Associated Gene Amplification in Chinese Hamster, Mouse Sarcoma, and Human Neuroblastoma Cells

In some cases, particularly when dealing with classic antimetabolites such as the folate antagonist methotrexate, selection yields cells that display a monospecific resistance to the drug used for selection or to its analogs; cross-resistance to other agents is, for the most part, not observed.

Drug Resistance: New Approaches to Treatment

Mechanisms by which malignant cells may become resistant to chemotherapeutic agents are reviewed, with emphasis on methotrexate resistance and a strategy for selectively eradicating these resistant cells with second generation antifolates that are cytotoxic to resistant cells is discussed.

The acquisition of methotrexate resistance by gene amplification

This paper will summarize studies from the authors’ laboratory concerning the acquisition of resistance to methotrexate (MTX).

Methotrexate resistant cells as targets for selective chemotherapy.

Genetics of drug resistance.

The advent of recombinant DNA technology as applied to mammalian cells, the recognition of the dynamic flexibility of the genome as in gene amplification, and the growing body of knowledge of the complexity and multiplicity of pathways governing cellular response have now provided other possible explanations for resistance development in addition to genotypic alteration.

Tumour cell resistance to anthracyclines — A review

Clinical testing of some of the therapeutic possibilities for circumventing anthracycline resistance may soon be appropriate, following inherited changes in the cell membrane resulting in failure of drug accumulation.

Multidrug resistance in human tumors.

  • A. Fojo
  • Biology, Chemistry
    Cancer treatment and research
  • 1989
A set of traits that comprise the multidrug resistance phenotype are recognized, including cross-resistance to a variety of natural products that are structurally unrelated and include at a minimum, the vinca alkaloids and colchicine, actinomycin D, the anthracyclines, and the epipodophyllotoxins.

Enhancement of the loss of multiple drug resistance by hydroxyurea.

Results indicate that, after removing selective pressure, hydroxyurea accelerates loss of resistance to vin Blastine and increases accumulation of vinblastine in KBV1 cells, presumably by accelerating loss of amplified mdr1 genes and thus P glycoprotein.



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.

Metaphase chromosome anomaly: association with drug resistance and cell-specific products.

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.

Amplification of the metallothionein-I gene in cadmium-resistant mouse cells.

  • L. BeachR. Palmiter
  • Biology
    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.

Karyotypic analysis of methotrexate-resistant and sensitive mouse L5178Y cells.

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).