inhibition, of topoisomerases : Anticancer Drugs

Inhibition, of  topoisomerases : Anticancer Drugs 


Topoisomerases arc potent targets of a variety of anticancer drugs. As the oncogenic cells undergo continuous division, they require continuous replication of cellular DNA. Topoisomerases are essential in replication for replication bubble formation, accurate daughter DNA separation and organization of new DNA helix into folded chromtin structure. The enzymes use DNA breakage and religation to relieve torsional stress. Once single stranded or double stranded breaks arc induced, Topo I and II bind to these by formation of tyrosine phosphate linkage. The inhibitors of Topo I and II stabilizes this binding and prohibiting further religation, so that breaks do not heal. Most of the anticancer drugs involved in this process are inhibitors of Topo II (anthracyclins, ml toxantrone, epica tcchins, aza toxin, actinomycins etc.). One of the earliest plant derived drug, camptothecin inhibits Topo I activity. Some antibiotics like distamycin and santopin can inhibit both the topoisomerases. Mechanisms of action of these compounds differ from each other, either intercalation in DNA grooves at breakage site, interference with AT? binding or prohibiting strand passage.