Topoisomerase inhibitor

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerase (topoisomerase I and II), which is a type of enzyme that controls the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. Topoisomerase inhibitors are chemical compounds that block the action of topoisomerase (topoisomerase I and II), which is a type of enzyme that controls the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. In recent years, topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently leads to apoptosis and cell death. Topoisomerase inhibitors can also function as antibacterial agents. Quinolones (including nalidixic acid and ciprofloxacin) have this function. Quinolones bind to these enzymes and prevent them from decatenation replicating DNA. Topoisomerase inhibitors are often divided according to which type of enzyme it inhibits. Numerous plant derived natural phenols (ex. EGCG, genistein, quercetin, resveratrol) possess strong topoisomerase inhibitory properties affecting both types of enzymes. They may express function of phytoalexins - compounds produced by plants to combat vermin and pests. Use of topoisomerase inhibitors for antineoplastic treatments may lead to secondary neoplasms because of DNA damaging properties of the compounds. Also plant derived polyphenols shows signs of carcinogenity, especially in fetuses and neonates who do not detoxify the compounds sufficiently. An association between high intake of tea (containing polyphenols) during pregnancy and elevated risk of childhood malignant central nervous system (CNS) tumours has been found. Human DNA topoisomerase I (Top1) is an essential enzyme that relaxes DNA supercoiling during replication and transcription. Top1 generates DNA single-strand breaks that allow rotation of the cleaved strand around the double helix axis. Top1 also religates the cleaved strand to reestablish intact duplex DNA.The Top1-DNA intermediates, known as cleavage complexes, are transient and at low levels under normal circumstances. However, treatment with Top1 inhibitors, such as the camptothecins, stabilize the cleavable complexes, prevent DNA religation and induce lethal DNA strand breaks. Cancer cells are selectively sensitive to the generation of these DNA lesions. Top1 is a validated target for the treatment of human cancers. Camptothecins are among the most effective anticancer agents recently introduced into clinical practice. In this regard, the camptothecin derivative topotecan (Hycamtin) is approved by the U.S. FDA for the treatment of ovarian and lung cancer. Another camptothecin derivative irinotecan (CPT11) is approved for the treatment of colon cancer. There are, however, certain clinical limitations of the camptothecin derivatives. These include: 1) spontaneous inactivation to a lactone form in blood, 2) rapid reversal of the trapped cleavable complex after drug removal, requiring prolonged infusions, 3) resistance of cancer cells overexpressing membrane transporters, and 4) dose-limiting side effects of diarrhea and neutropenia.