Novobiocin enhances alkylating agent cytotoxicity and DNA interstrand crosslinks in a murine model

Abstract

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 sixfold 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.