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Variable content of double minute chromosomes is not correlated with degree of phenotype instability in methotrexate-resistant human cell lines

Masters, Jeffrey and Keeley, Benneta and Gay, Helen and Attardi, Giuseppe (1982) Variable content of double minute chromosomes is not correlated with degree of phenotype instability in methotrexate-resistant human cell lines. Molecular and Cellular Biology, 2 (5). pp. 498-507. ISSN 0270-7306.

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Several variants resistant to 1.8 x 10(-4) M DL-methotrexate (MTX) have been isolated from the human cell lines HeLa BU25 and VA2-B by exposing them to progressively increasing concentrations of the drug. A striking variability of phenotype and chromosome constitution was observed among the different variants. All resistant cell lines exhibited a greatly increased dihydrofolic acid reductase (DHFR) activity and DHFR content; however, the DHFR activity levels varied considerably among the variants, ranging between about 35 and 275 times the parental level. In the absence of selective pressure, the increased DHFR activity was unstable, and in all cell lines but one was completely lost over a period ranging in different variants between 25 and 200 days. The MTX-resistant cells lines showed anomalies in their chromosome constitution, which involved the occurrence of a duplicated set of chromosomes in most cells of some of the variants and the presence of double minute chromosomes in all cell lines. An analysis of the correlation of loss of double minute chromosomes and loss of DHFR activity in the absence of MTX has given results consistent with the idea that the double-minute chromosomes contain amplified DHFR genes. However, the most significant finding is that, in contrast to what has been reported in the mouse system, the recognizable double-minute chromosomes varied greatly in number in different variants without any relationship to either the level of DHFR activity or the degree of instability of MTX resistance in the absence of selective pressure. These and other observations point to the occurrence in the human MTX-resistant variants of another set of DHFR genes, representing a varied proportion of the total, which is associated with the regular chromosomes, and which may be unstable in the absence of selective pressure.

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Additional Information:Copyright © 1982 by the American Society for Microbiology. Received 3 September 1981/Accepted 3 December 1981 These investigations were supported by Public Health Service grants GM-11726 and T32 GM-07616 from the National Institutes of Health. The HeLa BU25 cell line was generously provided by Saul Kit (Baylor University, Houston, Tex.). We are very grateful to Anne Chomyn, Carlo Morandi, Claus Doersen, and Barry Maurer for valuable discussions. The technical assistance of Arger Drew is gratefully acknowledged.
Issue or Number:5
Record Number:CaltechAUTHORS:MASmcb82
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6366
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Deposited On:05 Dec 2006
Last Modified:02 Oct 2019 23:32

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