Lack of drug-induced DNA cross-links in chlorambucil-resistant Chinese hamster ovary cells.
Chlorambucil (CLB) is an alkylating agent commonly used in the treatment of several neoplastic disorders. The mechanisms underlying resistance to this drug are not fully defined. We used the DNA alkaline elution technique to study cross-link formation in the wild type (K1) and a CLB-resistant (ChlR) Chinese hamster ovary cell line. [14C]CLB was used to measure drug uptake. The CLB-resistant cells were found to have negligible DNA cross-link formation compared to K1 cells at all time points tested. There was a correlation between the resistance to CLB and the decreased ability of resistant cells to form DNA cross-links. Results of drug uptake experiments excluded altered CLB accumulation as the basis for these findings. Assays of O6-alkylguanine transferase and topoisomerase. II provide evidence against a role of these enzymes in CLB resistance. These studies suggest that the mechanism of CLB cytotoxicity involves the formation of DNA cross-links. Reduced cross-link formation may confer resistance to CLB.
Jiang
B Z
BZ
Department of Medicine, New York University School of Medicine, New York 10016.
Bank
B B
BB
Hsiang
Y H
YH
Shen
T
T
Potmesil
M
M
Silber
R
R
D000818:Animals; D001692:Biological Transport; D002453:Cell Cycle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil; D006224:Cricetinae; D003432:Cross-Linking Reagents; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004351:Drug Resistance; D008780:Methyltransferases / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase
D003432:Cross-Linking Reagents; D002699:Chlorambucil; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004250:DNA Topoisomerases, Type II