Novobiocin enhances alkylating agent cytotoxicity and DNA interstrand crosslinks in a murine model.
Novobiocin enhances alkylating agent cytotoxicity and DNA interstrand crosslinks in a murine model.
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Novobiocin 在小鼠模型中增强烷化剂的细胞毒性和 DNA 链间交联。
DOI：
10.1172/jci112983
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发表时间：
1987
期刊：
影响因子：
--
通讯作者：
Schnipper,LE
中科院分区：
文献类型：
--
作者：
Eder,JP;Teicher,BA;Holden,SA;Cathcart,KN;Schnipper,LE
DNA-DNA交联是双功能烷基化剂细胞毒性的致死细胞机制。新生物素是一种DNA拓扑异构酶II的抑制剂，可损害烷基化剂加合物的真核DNA修复，并可能增加加合物的数量及其在恶性细胞中的细胞毒性。研究了新生物素对顺铂（cDDP）和卡莫司汀（BCNU）致克隆生存和DNA交联的影响。新生素对暴露于cDDP或BCNU的中国仓鼠卵巢细胞产生协同细胞毒性。新生物素和cDDP使DNA-DNA链间交联的形成比单独cDDP增加了6倍。效果与时间有关。新生物素和cDDP或BCNU显著降低小鼠纤维肉瘤的体内生长，而不增加宿主毒性。作为DNA-DNA交联引起的细胞毒性调节剂，新生物素可能会提高烷基化剂在人类癌症中的临床疗效，并为新的治疗策略提供新的见解。图片
DNA-DNA crosslinks are the lethal cellular mechanism of bifunctional alkylating agent cytotoxicity. Novobiocin, an inhibitor of DNA topoisomerase II, impairs eukaryotic DNA repair of alkylating agent adducts and may increase the number of adducts and their resultant cytotoxicity in malignant cells. The effect of novobiocin on clonogenic survival and DNA crosslinking due to cisplatin (cDDP) and carmustine (BCNU) was studied. Novobiocin caused synergistic cytotoxicity in Chinese hamster ovary cells exposed to cDDP or BCNU. Novobiocin and cDDP increased the formation of DNA-DNA interstrand crosslinks six-fold greater than cDDP alone. The effect was schedule dependent. Novobiocin and cDDP or BCNU markedly reduced in vivo growth of a murine fibrosarcoma without increased host toxicity. As a modulating agent of cytotoxicity due to DNA-DNA crosslinking, novobiocin may enhance the clinical effectiveness of the alkylating agents in human cancer and offer insight into new therapeutic strategies.Images