Targeting DNA topoisomerase II in cancer chemotherapy

The ability to interfere with topoisomerase II (TOP2) and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. Can recent studies lead to refined targeting of TOP2 and an improved anticancer strategy? Key Points Topoisomerase II (TOP2) is the target of several important classes of anticancer drugs, including the epipodophyllotoxin etoposide and the anthracycline doxorubicin. Most clinically active drugs that target TOP2 kill cells by trapping an enzyme intermediate termed the covalent complex. Therefore, the principal action of the TOP2-targeting drugs that are currently used is to generate enzyme-mediated DNA damage. A recent structure of the breakage reunion domain of TOP2 bound to DNA has been determined. This structure is likely to be useful for understanding the protein determinants of the action of drugs targeting TOP2. A drug–protein–DNA ternary complex would be valuable but has not yet been determined. TOP2-mediated DNA damage is repaired by multiple pathways. This DNA damage includes DNA strand breaks and proteins that are covalently bound to DNA. Repair of TOP2-mediated damage requires double-strand break repair pathways and other pathways that are specific for the removal of protein–DNA adducts. Sensitivity to TOP2-targeting drugs depends in part on the levels of TOP2. Cells overexpressing TOP2 are hypersensitive to TOP2 poisons and cells expressing low levels of TOP2 are drug resistant. TOP2A is frequently co-amplified with ERBB2 , which can lead to the development of tumours with increased levels of TOP2α. An important side effect of targeting TOP2 with TOP2 poisons is the formation of secondary malignancies that arise from drug-induced translocations. TOP2β might be the TOP2 isoform that is most responsible for the secondary malignancies caused by TOP2-targeting drugs. Anthracycline use is limited by cardiotoxicity. Although the mechanism of the cardiotoxicity is poorly understood, recent results suggest that anthracyclines that target TOP2β might contribute to cardiotoxicity. There might be considerable benefit to developing TOP2-targeting drugs that are specific for the TOP2α isoform. Catalytic inhibition of TOP2 could also be a useful anticancer strategy. New compounds are being developed to test this possibility. Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although