Tumor cell resistance to DNA topoisomerase II inhibitors: new developments

DNA topoisomerases are critical enzymes involved in replication, transcript ion, chromatin assembly and other aspects of DNA metabolism. They are also the targets of important anticancer drugs. The type II topoisomerases are s pecific targets of drug classes that comprise complex-stabilizing (epipodop hyllotoxins, anthracyclines) and catalytic (merbarone, bisdioxopiperazines) inhibitors. in this review,we update our current knowledge of resistance t o the antitumor inhibitors of the type II DNA topoisomerases, with special emphasis on the catalytic inhibitors, since novel catalytic inhibitor resis tant cell lines have only recently been described. Resistance to topoisomer ase II inhibitors can manifest as decreased or increased expression of or m utation in the topoisomerase II genes. However, the tumor cell's response t o exposure to these inhibitors involves more than the target enzyme, and th ese other responses are a major focus of this review. Such cellular changes are associated with and may contribute to the drug resistance phenotype. T hey involve decreased drug accumulation due to expression of membrane 'pump ' proteins, altered cytotoxic signaling through stress-activated protein ki nases,and alterations in apoptosis and cell cycle proteins (e.g. Bcl-2, Bar , p53, Rb). While it is evident that mutation in or altered expression of t he topoisomerase Il genes are sufficient to confer resistance to topoisomer ase 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 ho w these other cellular changes contribute to the drug resistance phenotype. (C) 1999 Harcourt Publishers Ltd.