DNA-interacting anticancer drugs were introduced in clinical practice about half a century ago. The early interpretation of their mechanism of action essentially relied on the covalent or reversible structural changes generated in the nucleic acid upon drug binding, especially through intercalative mechanisms, that impaired the basic functions of rapidly proliferating cancer (and normal) cells. Although this in part holds true even in the light of the present information, it became soon apparent that, in several instances, a more complicated series of processes caused cell death and that interaction with DNA was an accompanying aspect not necessarily connected with drug potency and therapy outcome [1]. A seminal breakthrough in cancer pharmacology was the discovery that the most important cytotoxic agents efficiently interacting with DNA were able to impair the functions of a family of DNA-processing essential enzymes present in all organisms, the topoisomerases (tops) [2]. This chapter will first deal with the structure and functions of tops and then focus on several pharmacologically relevant agents interfering with their activity. Since a number of recent exhaustive reviews are available on tops and top-directed agents [3-11], we will mainly discuss the latest advances in the field.
DNA topoisomerase-targeted drugs
PALUMBO, MANLIO;GATTO, BARBARA;SISSI, CLAUDIA
2002
Abstract
DNA-interacting anticancer drugs were introduced in clinical practice about half a century ago. The early interpretation of their mechanism of action essentially relied on the covalent or reversible structural changes generated in the nucleic acid upon drug binding, especially through intercalative mechanisms, that impaired the basic functions of rapidly proliferating cancer (and normal) cells. Although this in part holds true even in the light of the present information, it became soon apparent that, in several instances, a more complicated series of processes caused cell death and that interaction with DNA was an accompanying aspect not necessarily connected with drug potency and therapy outcome [1]. A seminal breakthrough in cancer pharmacology was the discovery that the most important cytotoxic agents efficiently interacting with DNA were able to impair the functions of a family of DNA-processing essential enzymes present in all organisms, the topoisomerases (tops) [2]. This chapter will first deal with the structure and functions of tops and then focus on several pharmacologically relevant agents interfering with their activity. Since a number of recent exhaustive reviews are available on tops and top-directed agents [3-11], we will mainly discuss the latest advances in the field.
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