Elevated topoisomerase II activity and altered chromatin in nitrogen mustard-resistant human cells.
A human Burkitt's lymphoma cell line (Raji-HN2) made resistant to nitrogen mustard, a bifunctional alkylating agent, was used to study the mechanism of resistance to nitrogen mustard. A comparative study of Raji-HN2 and the parental sensitive Raji cell lines revealed the following: (1) The DNA of Raji-HN2 cells was crosslinked by nitrogen mustard to a lower extent than Raji DNA; (2) once interstrand crosslinks were formed, they were repaired at the same rate in both cell lines; (3) DNA crosslink formation in Raji-HN2, but not in Raji cells, was enhanced by novobiocin, a topoisomerase II inhibitor; (4) Raji-HN2 cells had elevated topoisomerase II activity and were hypersensitive to topoisomerase inhibitors (amsacrine, novobiocin, teniposide); (5) similar amounts of topoisomerase I were found in both cell lines; and (6) the chromatin of Raji-HN2 but not of Raji cells, was hypersensitive to DNase I digestion. The relationship between DNA repair, topoisomerase II activity, chromatin structure and drug resistance is discussed.
Tan
K B
KB
Mattern
M R
MR
Boyce
R A
RA
Hertzberg
R P
RP
Schein
P S
PS
D000677:Amsacrine / Q000494:pharmacology*; D002051:Burkitt Lymphoma; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects* / Q000648:ultrastructure; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D008466:Mechlorethamine / Q000494:pharmacology*; D009675:Novobiocin / Q000494:pharmacology*; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013713:Teniposide / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D002843:Chromatin; D000677:Amsacrine; D009675:Novobiocin; D008466:Mechlorethamine; D013713:Teniposide; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin