Important differences between topoisomerase-I and -II targeting agents

Abstract

The twentieth century marked the discovery of numerous drugs with varying degrees of efficacy against rapidly dividing cancer cells. In the 1950's, the first of a new class of drugs, camptothecin was found to be a strong inhibitor of DNA synthesis. 1 Unfortunately, this early formulation had poor aqueous solubility and severe clinical toxicity. Years later, these solubility issues were corrected and more tolerable formulations such as topotecan were designed. 2,3 The paper by Huang and colleagues compares the molecular mechanism of action between a topoisomerase-I inhibitor topotecan, and a topoisomerase-II inhibitor mitoxantrone, pointing at important, therapy-relevant differences in their mechanism of action. 4 Despite demonstrated clinical efficacy, the exact target of DNA-synthesis inhibitors remained elusive until the 1980's, when reports emerged that camptothecin and its analogues interacted with DNA topoisomerase-I. 5,6 These topoisomerase enzymes have the ability to relax and untangle large strands of DNA by the process of transesterification. 7 Generation of this transient 'cleavable complex' relieves the torsional stress that develops in the DNA helix during replication and transcription. 7 It is proposed that drugs which interact with topoisomerase stabilize this cleavable complex and induce double-stranded DNA breaks upon collision of this complex with the moving replication fork, thereby ultimately leading to cell cycle arrest and apoptosis. 2,3,8 These topoisomerase-I targeting drugs appear more specific to the S or DNA synthesis specific phase of the cell cycle. 2,3 While topoisomerase-I causes single-strand DNA breaks, topoisomerase-II itself induces transient double-strand DNA breaks. Topoisomerase-II is crucial for chromosome condensation and segregation, and cells that lack this enzyme are rendered unviable. 7,9 Drugs such as doxorubicin and its analogue mitoxantrone partially exert their effect by targeting topoisomerase-II. 9,10 Unlike topoisomerase-I targeting drugs, topoisomerase-II inhibitors exert their effect throughout the cell cycle likely by interfering with both DNA and RNA polymerases. 10 Despite similar structures, mitoxantrone and doxorubicin have quite different levels of efficacy against common tumors. Mitoxantrone has a very narrow spectrum of activity restricted to breast, prostate, acute leukemia, and lymphoma, whereas doxorubicin has been proven to be active against a broad range of cancers ranging from numerous leukemic cell types to practically all solid organ tumors. 3,10 The toxicity profile, although similar, is far more dramatic for doxorubicin, particularly with respect to irreversible cardiomyopathy. These clinical toxicities are partly explained by doxorubicin's known effects such as DNA intercalation, inhibition of helicases, generation of reactive oxygen species (ROS), release of cellular iron, and stabilization of topoisomerase II. 9,10 As revealed by its clinical efficacy, mitoxantrone's mechanism of action, although likely similar to that of doxorubicin, has s...