Tumor cell resistance to DNA topoisomerase II inhibitors: new developments

DNA topoisomerases are critical enzymes involved in replication, transcription, chromatin assembly and other aspects of DNA metabolism. They are also the targets of important anticancer drugs. The type II topoisomerases are specific targets of drug classes that comprise complex-stabilizing (epipodophyllotoxins, anthracyclines) and catalytic (merbarone, bisdioxopiperazines) inhibitors. In this review, we update our current knowledge of resistance to the antitumor inhibitors of the type II DNA topoisomerases, with special emphasis on the catalytic inhibitors, since novel catalytic inhibitor resistant cell lines have only recently been described. Resistance to topoisomerase II inhibitors can manifest as decreased or increased expression of or mutation in the topoisomerase II genes. However, the tumor cell's response to exposure to these inhibitors involves more than the target enzyme, and these other responses are a major focus of this review. Such cellular changes are associated with and may contribute to the drug resistance phenotype. They involve decreased drug accumulation due to expression of membrane 'pump' proteins, altered cytotoxic signaling through stress-activated protein kinases, and alterations in apoptosis and cell cycle proteins (e.g. Bcl-2, Bax, p53, Rb). While it is evident that mutation in or altered expression of the topoisomerase II genes are sufficient to confer resistance to topoisomerase inhibitors, it is not clear whether the other changes are a consequence of the selection or a response to the cytotoxic insult, nor is it clear how these other cellular changes contribute to the drug resistance phenotype. Copyright 1999 Harcourt Publishers Ltd.