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

Smitha Antony; Glenda Kohlhagen; Keli Agama; Muthusamy Jayaraman; Shousong Cao; Farukh A Durrani; Youcef M Rustum; Mark Cushman; Yves Pommier

doi:10.1124/mol.104.003889

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

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

Smitha Antony, Glenda Kohlhagen, Keli Agama, Muthusamy Jayaraman, Shousong Cao, Farukh A Durrani, Youcef M Rustum, Mark Cushman and Yves Pommier

Molecular pharmacology, Vol.67(2), pp.523-530

02/01/2005

DOI: 10.1124/mol.104.003889

PMID: 15531731

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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.

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Title: Subtitle: Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison
Creators: Smitha Antony - National Cancer Institute
Glenda Kohlhagen
Keli Agama
Muthusamy Jayaraman
Shousong Cao
Farukh A Durrani
Youcef M Rustum
Mark Cushman
Yves Pommier - National Institutes of Health
Resource Type: Journal article
Publication Details: Molecular pharmacology, Vol.67(2), pp.523-530
DOI: 10.1124/mol.104.003889
PMID: 15531731
ISSN: 0026-895X
eISSN: 1521-0111
Language: English
Date published: 02/01/2005
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359573702771

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