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 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.
Tan
K B
KB
Department of Molecular Pharmacology, Smith Kline & French Laboratories, Philadelphia, PA 19101.
Mattern
M R
MR
Boyce
R A
RA
Schein
P S
PS
D000970:Antineoplastic Agents / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000201:enzymology; D002460:Cell Line; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004351:Drug Resistance; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008466:Mechlorethamine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D008466:Mechlorethamine; D004250:DNA Topoisomerases, Type II; D005978:Glutathione