Ishida R, Nishizawa M, Nishimoto T, Takahashi T
Laboratory of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Japan.
Somat Cell Mol Genet. 1988 Sep;14(5):489-97. doi: 10.1007/BF01534714.
A novobiocin-resistant BHK cell line, designated as NovrA2, was found to exhibit cross-resistance to other topoisomerase II inhibitors such as 4'-dimethylepipodophyllotoxin-4-(4,6-O-ethylidine-beta-D-glu copyranoside) (VP-16), adriamycin, and 4'-(9-acridinyl-amino)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).
一种对新生霉素耐药的BHK细胞系，命名为NovrA2，被发现对其他拓扑异构酶II抑制剂如4'-二甲基表鬼臼毒素-4-(4,6-O-亚乙基-β-D-吡喃葡萄糖苷)(VP-16)、阿霉素和4'-(9-吖啶基氨基)甲磺酰间茴香胺(m-AMSA)表现出交叉耐药，并且对不同类型的药物如长春碱和阿糖胞苷也有交叉耐药。NovrA2细胞系的耐萘啶酸细胞(A2Nalr)在表型上恢复为对新生霉素敏感，类似于野生型细胞，并且对VP-16和阿霉素的敏感性也部分恢复，但对长春碱和阿糖胞苷不敏感。当将VP-16添加到细胞培养物中时，NovrA2细胞中药物诱导的DNA链断裂比BHK细胞中少得多。NovrA2细胞中这种链断裂水平的降低不是由于药物摄取减少，因为这两种细胞系积累的放射性标记VP-16水平相似。与BHK细胞相比，VP-16在NovrA2细胞分离的细胞核中诱导的DNA断裂也更少。从BHK和Novr细胞中部分纯化的拓扑异构酶II的VP-16诱导的DNA切割活性没有显著差异。这些结果表明，NovrA2细胞对各种药物的耐药性不是通过与膜通透性相关的防御机制获得的，并且表明NovrA2细胞对拓扑异构酶II抑制剂的耐药性可能部分归因于拓扑异构酶II相关因子的改变。
