Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison.

Abstract

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.

• Authors: Smitha Antony, Glenda Kohlhagen, Keli Agama, Muthusamy Jayaraman, Shousong Cao, Farukh A Durrani, Youcef M Rustum, Mark Cushman, Yves Pommier
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 67 Issue 2 Pg. 523-30 (Feb 2005) ISSN: 0026-895X [Print] United States
• PMID: 15531731 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 6-(3-(2-hydroxyethyl)amino-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno(1,2-)isoquinoline
• Enzyme Inhibitors
• Growth Inhibitors
• Indenes
• Isoquinolines
• Topoisomerase I Inhibitors
• DNA Topoisomerases, Type I

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type I (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Growth Inhibitors (pharmacology, poisoning)
• Humans
• Indenes (pharmacology, poisoning)
• Insecta
• Isoquinolines (pharmacology, poisoning)
• Mice
• Mice, Nude
• Topoisomerase I Inhibitors
• Xenograft Model Antitumor Assays (methods)