Abstract
Abstract Camptothecins are effective against previously resistant tumors. Because camptothecins are presently the only class of topoisomerase I (Top1) inhibitors approved for cancer treatment, and because camptothecins have limitations including dose-limiting toxicity, chemical instability, and are susceptible to drug efflux transporter, we developed the indenoisoquinolines. Like camptothecins, the indenoisoquinolines selectively trap Top1-DNA cleavage complexes and have been co-crystallized with the Top1-DNA cleavage complexes. Indenoisoquinolines show antitumor activity in animal models. They have several advantages over the camptothecins: 1) They are synthetic and chemically stable (unlike camptothecins); 2) The Top1 cleavage sites trapped by the indenoisoquinolines have different genomic locations than camptothecins, implying differential targeting of cancer cell genomes; 3) The Top1 cleavage complexes trapped by indenoisoquinolines are more stable than for camptothecins, indicative of prolonged drug action; and 4) They are less or not substrates for the multidrug resistance efflux pumps (ABCG2 and MDR-1). Among the more than 400 indenoisoquinolines synthesized and evaluated, three have been retained as leads for clinical development by the NCI: NSC 706744, NSC 725776 (Indimitecan) and NSC 724998 (Indotecan). The trapping of Top1 cleavage complexes by indenoisoquinolines in cells results in the rapid and sustained phosphorylation of histone H2AX (referred to as -H2AX). We will also discuss the other class of non-camptothecin Top1 inhibitors GENZ644283 (see abstract by D. Sooryakumar) and the use of -H2AX as a pharmacodynamic biomarker for the clinical development of the non-camptothecin Top1 inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN08-04.
Published Version
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