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DNA replication, transcription, and chromosome condensation require enzymes that can regulate the topological changes occurring in DNA following these processes. Topoisomerases are such enzymes. These catalyze the cleavage of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), the passage of DNA through the resulting break, and the rejoining of the broken phosphodiester backbone. Chemical agents able to interfere with these enzymes present in the cancer cells have outstanding therapeutic efficacy in human cancer. Camptothecin derivatives (acting on type IB topoisomerases) have been shown to stimulate DNA cleavage by topoisomerases leading to cell death by apoptosis, but they are not always specific to tumor cells; they are also toxic and there’s much resistance to them. That is why right now there is considerable interest in improving the selectivity of these agents by making them sequence specific. Another way to improve the therapeutic efficacy of the drugs is inactivation of NF-κB molecule which is a negative regulator of apoptosis in cancer cells. There is also considerable interest in developing new non-camptothecin drugs that would also inhibit topoisomerases I but in a more efficient and less toxic manner. In summary, the topoisomerase inhibitors are effective anti-cancer agents to some extent, but the current research focuses on improving their efficacy and selectivity and possibly replacing them altogether with better novel topoisomerase I poisons.