TY - JOUR T1 - Cellular Topoisomerase I Inhibition and Antiproliferative Activity by MJ-III-65 (NSC 706744), an Indenoisoquinoline Topoisomerase I Poison JF - Molecular Pharmacology JO - Mol Pharmacol SP - 523 LP - 530 DO - 10.1124/mol.104.003889 VL - 67 IS - 2 AU - Smitha Antony AU - Glenda Kohlhagen AU - Keli Agama AU - Muthusamy Jayaraman AU - Shousong Cao AU - Farukh A. Durrani AU - Youcef M. Rustum AU - Mark Cushman AU - Yves Pommier Y1 - 2005/02/01 UR - http://molpharm.aspetjournals.org/content/67/2/523.abstract N2 - To overcome camptothecin's (CPT) lactone instability, reversibility of the drug-target interaction, and drug resistance, attempts to synthesize compounds that are CPT-like in their specificity and potency yet display a unique profile have been underway. In this pursuit, we have identified one of the idenoisoquinoline derivatives, MJ-III-65 (NSC 706744; 6-[3-(2-hydroxyethyl)amino-1-propyl]-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline) with both similarities and differences from CPT. MJ-III-65 traps topoisomerase I (Top1) reversibly like CPT but with different DNA sequence preferences. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with MJ-III-65 at nanomolar concentrations. These MJ-III-65-induced protein-linked DNA breaks were resistant to reversal after an hour of drug removal, compared with CPT, which completely reversed. Studies in human cells in culture found MJ-III-65 to be cytotoxic. Furthermore, limited cross-resistance was observed in camptothecin-resistant cell lines. MJ-III-65 also exhibits antitumor activity in mouse tumor xenografts. ER -