DNA topoisomerases in cancer chemotherapy: using enzymes to generate selective DNA damage.
DNA topoisomerase II targeting agents such as etoposide and doxorubicin are well-established cancer chemotherapeutic agents. Topotecan (Hycamtin) and irinotecan (Camptosar) are launched drugs that target topoisomerase I and have significant activity against many solid malignancies. These agents have important mechanistic similarities, converting their target enzyme(s) to generate DNA damage. Recent structural and biochemical studies on targeting of topoisomerases by antitumor agents are providing a framework for understanding drug action at the enzyme level, and at the level of cellular pathways important for responses to this unique type of DNA damage. These investigations into the mechanisms of action of topoisomerase-targeting agents should aid in the design of dinical protocols that optimize the activity of these agents.
Nitiss
John L
JL
Molecular Pharmacology Department, St Jude Children's Research Hospital, Memphis, TN 38105, USA. john.nitiss@stjude.org
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D059003:Topoisomerase Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059003:Topoisomerase Inhibitors