Correlation of double-minute chromosomes with unstable multidrug cross-resistance in uptake mutants of neuroblastoma cells

F. Baskin, R. N. Rosenberg, V. Dev

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Abstract

A series of increasingly drug-resistant cell populations were selected and cloned from C-46 murine neuroblastoma with the chemotherapeutic drugs maytansine, vincristine, adriamycin, or Baker's antifol. All clones demonstrated reciprocal cross-resistance to these structurally and functionally diverse drugs and failed to accumulate radiolabeled vincristine, colchicine, or Baker's antifol despite normal drug binding to cell homogenates. Initial isolates of drug-resistant populations were genetically unstable, rapidly reverting to a drug-sensitive phenotype when grown without drug, at 0.05 reversion per cell division. After prolonged growth in drug, this drug-resistant genotype stabilized. Mean chromosome number increased 300% in an initially isolated 20-fold maytansine-resistant clone, which also displayed numerous double-minute chromosomes. Descendants 240-fold more resistant than the parent, also unstable, possessed the wild-type complement of 80 chromosomes, but 45% of these cells possessed 24 double-minute chromosomes per cell, such chromosomes were absent from the drug-sensitive parental clone. Only 1.0 and 1.2 double-minute chromosomes per cell were seen in a 7-fold stably resistant revertant or 1200-fold stably resistant descendants, respectively. Double-minute chromosomes containing amplified genes for the drug target dihydrofolate reductase (tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) have been reported in an unstable methotrexate-resistant RI-A sarcoma. These extrachromosomal gene copies were absent in stably resistant progeny. The presence of similar particles in unstably drug-resistant uptake mutants of neuroblastoma and their diminution in stably resistant descendants supports and extends their possible role in the rapid onset and instability of epigenetic drug resistance in cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)3654-3658
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume78
Issue number6 I
StatePublished - 1981

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Multiple Drug Resistance
Neuroblastoma
Chromosomes
Pharmaceutical Preparations
triazinate
Tetrahydrofolate Dehydrogenase
Maytansine
Clone Cells
Vincristine
Colchicine
Drug Resistance
Epigenomics
Methotrexate
Sarcoma
Cell Division
Doxorubicin
Population
Genes
Genotype
Phenotype

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

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title = "Correlation of double-minute chromosomes with unstable multidrug cross-resistance in uptake mutants of neuroblastoma cells",
abstract = "A series of increasingly drug-resistant cell populations were selected and cloned from C-46 murine neuroblastoma with the chemotherapeutic drugs maytansine, vincristine, adriamycin, or Baker's antifol. All clones demonstrated reciprocal cross-resistance to these structurally and functionally diverse drugs and failed to accumulate radiolabeled vincristine, colchicine, or Baker's antifol despite normal drug binding to cell homogenates. Initial isolates of drug-resistant populations were genetically unstable, rapidly reverting to a drug-sensitive phenotype when grown without drug, at 0.05 reversion per cell division. After prolonged growth in drug, this drug-resistant genotype stabilized. Mean chromosome number increased 300{\%} in an initially isolated 20-fold maytansine-resistant clone, which also displayed numerous double-minute chromosomes. Descendants 240-fold more resistant than the parent, also unstable, possessed the wild-type complement of 80 chromosomes, but 45{\%} of these cells possessed 24 double-minute chromosomes per cell, such chromosomes were absent from the drug-sensitive parental clone. Only 1.0 and 1.2 double-minute chromosomes per cell were seen in a 7-fold stably resistant revertant or 1200-fold stably resistant descendants, respectively. Double-minute chromosomes containing amplified genes for the drug target dihydrofolate reductase (tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) have been reported in an unstable methotrexate-resistant RI-A sarcoma. These extrachromosomal gene copies were absent in stably resistant progeny. The presence of similar particles in unstably drug-resistant uptake mutants of neuroblastoma and their diminution in stably resistant descendants supports and extends their possible role in the rapid onset and instability of epigenetic drug resistance in cancer chemotherapy.",
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T1 - Correlation of double-minute chromosomes with unstable multidrug cross-resistance in uptake mutants of neuroblastoma cells

AU - Baskin, F.

AU - Rosenberg, R. N.

AU - Dev, V.

PY - 1981

Y1 - 1981

N2 - A series of increasingly drug-resistant cell populations were selected and cloned from C-46 murine neuroblastoma with the chemotherapeutic drugs maytansine, vincristine, adriamycin, or Baker's antifol. All clones demonstrated reciprocal cross-resistance to these structurally and functionally diverse drugs and failed to accumulate radiolabeled vincristine, colchicine, or Baker's antifol despite normal drug binding to cell homogenates. Initial isolates of drug-resistant populations were genetically unstable, rapidly reverting to a drug-sensitive phenotype when grown without drug, at 0.05 reversion per cell division. After prolonged growth in drug, this drug-resistant genotype stabilized. Mean chromosome number increased 300% in an initially isolated 20-fold maytansine-resistant clone, which also displayed numerous double-minute chromosomes. Descendants 240-fold more resistant than the parent, also unstable, possessed the wild-type complement of 80 chromosomes, but 45% of these cells possessed 24 double-minute chromosomes per cell, such chromosomes were absent from the drug-sensitive parental clone. Only 1.0 and 1.2 double-minute chromosomes per cell were seen in a 7-fold stably resistant revertant or 1200-fold stably resistant descendants, respectively. Double-minute chromosomes containing amplified genes for the drug target dihydrofolate reductase (tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) have been reported in an unstable methotrexate-resistant RI-A sarcoma. These extrachromosomal gene copies were absent in stably resistant progeny. The presence of similar particles in unstably drug-resistant uptake mutants of neuroblastoma and their diminution in stably resistant descendants supports and extends their possible role in the rapid onset and instability of epigenetic drug resistance in cancer chemotherapy.

AB - A series of increasingly drug-resistant cell populations were selected and cloned from C-46 murine neuroblastoma with the chemotherapeutic drugs maytansine, vincristine, adriamycin, or Baker's antifol. All clones demonstrated reciprocal cross-resistance to these structurally and functionally diverse drugs and failed to accumulate radiolabeled vincristine, colchicine, or Baker's antifol despite normal drug binding to cell homogenates. Initial isolates of drug-resistant populations were genetically unstable, rapidly reverting to a drug-sensitive phenotype when grown without drug, at 0.05 reversion per cell division. After prolonged growth in drug, this drug-resistant genotype stabilized. Mean chromosome number increased 300% in an initially isolated 20-fold maytansine-resistant clone, which also displayed numerous double-minute chromosomes. Descendants 240-fold more resistant than the parent, also unstable, possessed the wild-type complement of 80 chromosomes, but 45% of these cells possessed 24 double-minute chromosomes per cell, such chromosomes were absent from the drug-sensitive parental clone. Only 1.0 and 1.2 double-minute chromosomes per cell were seen in a 7-fold stably resistant revertant or 1200-fold stably resistant descendants, respectively. Double-minute chromosomes containing amplified genes for the drug target dihydrofolate reductase (tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) have been reported in an unstable methotrexate-resistant RI-A sarcoma. These extrachromosomal gene copies were absent in stably resistant progeny. The presence of similar particles in unstably drug-resistant uptake mutants of neuroblastoma and their diminution in stably resistant descendants supports and extends their possible role in the rapid onset and instability of epigenetic drug resistance in cancer chemotherapy.

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