Hydroxyurea accelerates loss of extrachromosomally amplified genes from tumor cells.
Gene amplification is one mechanism mediating the resistance of tumor cells to antineoplastic agents and the overexpression of a variety of oncogenes in diverse tumor types. There is mounting evidence that acentric extrachromosomal elements such as double minute chromosomes are common intermediates in the amplification process. These acentric structures partition unequally at mitosis and can be lost in the absence of selection. In the present study, we used human and hamster cell lines documented to contain extrachromosomally amplified drug resistance genes to investigate the feasibility of enhancing the loss rate of the extrachromosomally amplified genes to make the cells more sensitive to drug treatment. The results show that treatment of each of these lines with hydroxyurea accelerates the loss of the extrachromosomally amplified drug resistance genes. Loss of these extrachromosomal genes was associated with a corresponding increase in the drug sensitivity in the cases examined. The mechanism of accelerated loss does not appear to involve a differential effect on the replication of extrachromosomal DNA sequences. The results suggest that hydroxyurea treatment may provide a valuable tool for the general accelerated elimination of extrachromosomally amplified genes.
Von Hoff
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DD
Department of Medicine, University of Texas Health Science Center, San Antonio 78284.
Waddelow
T
T
Forseth
B
B
Davidson
K
K
Scott
J
J
Wahl
G
G
D001221:Aspartate Carbamoyltransferase / Q000235:genetics; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002872:Chromosome Deletion; D004261:DNA Replication / Q000187:drug effects; D004080:Dihydroorotase / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005784:Gene Amplification / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D008727:Methotrexate / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000235:genetics; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010957:Plasmids / Q000187:drug effects* / Q000235:genetics; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
C033626:CAD trifunctional enzyme; D009097:Multienzyme Complexes; D001224:Aspartic Acid; D014747:Vinblastine; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D010746:Phosphonoacetic Acid; D006918:Hydroxyurea; D008727:Methotrexate