title: Sequence-specific interactions of drugs interfering with the topoisomerase-DNA cleavage complex.
abstract: DNA-processing enzymes, such as the topoisomerases (tops), represent major targets for potent anticancer (and antibacterial) agents. The drugs kill cells by poisoning the enzymes' catalytic cycle. Understanding the molecular details of top poisoning is a fundamental requisite for the rational development of novel, more effective antineoplastic drugs. In this connection, sequence-specific recognition of the top-DNA complex is a key step to preferentially direct the action of the drugs onto selected genomic sequences. In fact, the (reversible) interference of drugs with the top-DNA complex exhibits well-defined preferences for DNA bases in the proximity of the cleavage site, each drug showing peculiarities connected to its structural features. A second level of selectivity can be observed when chemically reactive groups are present in the structure of the top-directed drug. In this case, the enzyme recognizes or generates a unique site for covalent drug-DNA binding. This will further subtly modulate the drug's efficiency in stimulating DNA damage at selected sites. Finally, drugs can discriminate not only among different types of tops, but also among different isoenzymes, providing an additional level of specific selection. Once the molecular basis for DNA sequence-dependent recognition has been established, the above-mentioned modes to generate selectivity in drug poisoning can be rationally exploited, alone or in combination, to develop tailor-made drugs targeted at defined loci in cancer cells.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padua, Italy. manlio.palumbo@unipd.it
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013379:Substrate Specificity; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I