Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison.
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.
Antony
Smitha
S
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Dr., National Institutes of Health, Bethesda, MD 20892, USA.
Kohlhagen
Glenda
G
Agama
Keli
K
Jayaraman
Muthusamy
M
Cao
Shousong
S
Durrani
Farukh A
FA
Rustum
Youcef M
YM
Cushman
Mark
M
Pommier
Yves
Y
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000506:poisoning; D006801:Humans; D007192:Indenes / Q000494:pharmacology* / Q000506:poisoning; D007313:Insecta; D007546:Isoquinolines / Q000494:pharmacology* / Q000506:poisoning; D051379:Mice; D008819:Mice, Nude; D059004:Topoisomerase I Inhibitors; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C415158:6-(3-(2-hydroxyethyl)amino-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno(1,2-)isoquinoline; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I