title: Intercalator-induced, topoisomerase II-mediated DNA cleavage and its modification by antineoplastic antimetabolites.
abstract: Defining specific biochemical targets of active antineoplastic agents could aid in discovering better anticancer therapy and more thoroughly understanding the biochemical basis of malignancy. Through a series of cellular and biochemical studies, we and others have identified the nuclear enzyme topoisomerase II as the target of several active agents, including 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA). The interference with topoisomerase II produced by m-AMSA can be quantified in whole cells exposed to m-AMSA by using the alkaline elution technique to measure DNA cleavage. Antimetabolites such as ara-C, hydroxyurea, and 5-azacytidine can augment m-AMSA-induced, topoisomerase II-mediated DNA cleavage and, concurrently, m-AMSA-induced cell killing. Studies in proliferating and quiescent human cells and an m-AMSA-sensitive/resistant human leukemia cell pair further support the hypothesis that a connection exists between topoisomerase II-mediated DNA cleavage and the mechanism by which m-AMSA kills cells. Pharmacologic or hormonal modification of specific biochemical processes critical to drug-induced cytotoxicity may enhance the therapeutic index of clinically useful agents.
mesh_terms: D000609:Aminoacridines / Q000494:pharmacology; D000677:Amsacrine; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA; D004250:DNA Topoisomerases, Type II / Q000502:physiology*; D004357:Drug Synergism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D066298:In Vitro Techniques; D007364:Intercalating Agents / Q000494:pharmacology*; D051379:Mice
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D000677:Amsacrine; D003561:Cytarabine; D004247:DNA; D004250:DNA Topoisomerases, Type II; D001374:Azacitidine; D006918:Hydroxyurea