Cross-resistance of novobiocin-resistant BHK cell line to topoisomerase II inhibitors

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Abstract
A novobiocin-resistant BHK cell line, designated as Novr A2, was found to exhibit cross-resistance to other topoisomerase II inhibitors such as 4′-dimethylepipodophyllotoxin-4-(4,6-O-ethylidine-β-d-glucopyranoside) (VP-16), adriamycin, and 4′-(9-acridinyl-ami-no)methanesulfon-m-anisidide (m-AMSA), and also to different types of drugs such as vinblastine and arabinocytidine. Nalidixic acid-resistant cells (A2Nalr) of the NovrA2 cell line were phenotypically reverted to novobiocin sensitivity like wild-type cells and were also partially reverted to sensitivity to VP-16 and adriamycin, but not to vinblastine and arabinocytidine. When VP-16 was added to cell culture, the drug-induced DNA strand breaks were much fewer in NovrA2 cells than in BHK cells. This reduced level of strand breaks in NovrA2 cells was not due to reduced drug uptake, because the two cell lines accumulated similar levels of radiolabeled VP-16. VP-16 also induced fewer DNA breaks in isolated nuclei of NovrA2 cells than in those of BHK cells. There was no significant difference in the VP-16-induced DNA cleavage activities of partially purified topoisomerase II from BHK and Novr cells. These results show that the resistance of NovrA2 cells to various drugs is not acquired by a defense mechanism related to membrane permeability and suggest that the resistance of the NovrA2 cells to topoisomerase II inhibitors might be due in part to alteration in a topoisomerase II associated factor(s).