Elevated DNA Topoisomerase II Activity in Nitrogen Mustard-Resistant Human Cells

A human Burkitt lymphoma cell line, Raji-HN2, made 10-fold more resistant to nitrogen mustard (HN2) than the parental Raji cell line, exhibited the following characteristics when compared to the parental Raji cells: (i) decreased HN2-induced DNA interstrand crosslinking; (ii) increased (3-fold) DNA...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 84; no. 21; pp. 7668 - 7671
Main Authors Tan, K. B., Mattern, M. R., Boyce, R. A., Schein, P. S.
Format Journal Article
LanguageEnglish
Published Washington, DC National Academy of Sciences of the United States of America 01.11.1987
National Acad Sciences
Subjects
Antineoplastic Agents - pharmacology
Biological and medical sciences
Burkitt Lymphoma - enzymology
Cell growth
Cell Line
Cell lines
Cell physiology
Crosslinking
DNA
DNA Repair
DNA Topoisomerases, Type II - metabolism
Drug Resistance
Elution
Fundamental and applied biological sciences. Psychology
Glutathione - metabolism
Humans
Kinetics
Lymphocytes
Mechlorethamine - pharmacology
Miscellaneous
Molecular and cellular biology
Nitrogen
Phenotypes
Tumor cell line
Human origin
Resistance
Cell culture
DNA topoisomerase (ATP-hydrolysing)
DNA
Repair
Mechanism
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Summary:A human Burkitt lymphoma cell line, Raji-HN2, made 10-fold more resistant to nitrogen mustard (HN2) than the parental Raji cell line, exhibited the following characteristics when compared to the parental Raji cells: (i) decreased HN2-induced DNA interstrand crosslinking; (ii) increased (3-fold) DNA topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.3] activity; (iii) increased (4- to 11-fold) sensitivity to topoisomerase II inhibitors; (iv) increased (2-fold) glutathione content; and (v) increased (2-fold) cell doubling time. The resistant phenotype was unstable and was maintained by weekly treatment of the cells with HN2. Growing the resistant cells in the absence of HN2 resulted in a time-dependent decrease in both resistance to HN2 and topoisomerase II activity and an increase in DNA interstrand crosslinking induced by HN2. We hypothesize that HN2 resistance is due to enhanced monoadduct repair with resultant decreased DNA crosslinking and that this process is mediated by topoisomerase II.
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ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.84.21.7668