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Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I.
Cancer Res. 2003 Nov 01; 63(21):7428-35.CR

Abstract

Camptothecin (CPT) and its derivatives target mammalian DNA topoisomerase I (top1) and are among the most effective novel anticancer drugs. However, the activity of CPTs is limited by several factors, including drug inactivation by lactone ring opening, tumor drug resistance, and toxicity in patients. Novel top1 inhibitors are being searched to overcome such limitations and expand the anticancer spectrum of camptothecins. MJ-III-65 (NSC 706744) is among the most promising indenoisoquinolines to date. In this study, we show that MJ-III-65 enhances top1 cleavage complexes by both inhibiting their reversal (religation) more efficiently than CPT and by enhancing their formation. The top1 DNA cleavage complexes induced by MJ-III-65 exhibit a different distribution pattern compared with CPT and exhibit different base sequence preferences immediately around the top1 cleavage sites. Although CPTs have a preference for thymine at the (-1) position and guanine at the (+1) position of the top1-mediated DNA cleavage sites, MJ-III-65 can accommodate different base pairs at the (-1), (+1), or (+2) position, with a preference for a cytosine at the (-1) position on the scissile strand. Another difference with CPTs is the activity of MJ-III-65 against CPT-resistant top1 enzymes, implying that the amino acid residue interactions with top1 are different for MJ-III-65 and CPTs. As with CPT, MJ-III-65 is inactive against vaccinia top1. This study shows the specific molecular interactions of MJ-III-65 with top1 and demonstrates that MJ-III-65 is a potentially useful top1 inhibitor that enhances and traps top1 cleavage sites not sensitive to CPTs.

Authors+Show Affiliations

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute/NIH, 37 Convent Drive, Bethesda, MD 20892-4255, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14612542

Citation

Antony, Smitha, et al. "Differential Induction of Topoisomerase I-DNA Cleavage Complexes By the Indenoisoquinoline MJ-III-65 (NSC 706744) and Camptothecin: Base Sequence Analysis and Activity Against Camptothecin-resistant Topoisomerases I." Cancer Research, vol. 63, no. 21, 2003, pp. 7428-35.
Antony S, Jayaraman M, Laco G, et al. Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I. Cancer Res. 2003;63(21):7428-35.
Antony, S., Jayaraman, M., Laco, G., Kohlhagen, G., Kohn, K. W., Cushman, M., & Pommier, Y. (2003). Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I. Cancer Research, 63(21), 7428-35.
Antony S, et al. Differential Induction of Topoisomerase I-DNA Cleavage Complexes By the Indenoisoquinoline MJ-III-65 (NSC 706744) and Camptothecin: Base Sequence Analysis and Activity Against Camptothecin-resistant Topoisomerases I. Cancer Res. 2003 Nov 1;63(21):7428-35. PubMed PMID: 14612542.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I. AU - Antony,Smitha, AU - Jayaraman,Muthusamy, AU - Laco,Gary, AU - Kohlhagen,Glenda, AU - Kohn,Kurt W, AU - Cushman,Mark, AU - Pommier,Yves, PY - 2003/11/13/pubmed PY - 2004/1/17/medline PY - 2003/11/13/entrez SP - 7428 EP - 35 JF - Cancer research JO - Cancer Res VL - 63 IS - 21 N2 - Camptothecin (CPT) and its derivatives target mammalian DNA topoisomerase I (top1) and are among the most effective novel anticancer drugs. However, the activity of CPTs is limited by several factors, including drug inactivation by lactone ring opening, tumor drug resistance, and toxicity in patients. Novel top1 inhibitors are being searched to overcome such limitations and expand the anticancer spectrum of camptothecins. MJ-III-65 (NSC 706744) is among the most promising indenoisoquinolines to date. In this study, we show that MJ-III-65 enhances top1 cleavage complexes by both inhibiting their reversal (religation) more efficiently than CPT and by enhancing their formation. The top1 DNA cleavage complexes induced by MJ-III-65 exhibit a different distribution pattern compared with CPT and exhibit different base sequence preferences immediately around the top1 cleavage sites. Although CPTs have a preference for thymine at the (-1) position and guanine at the (+1) position of the top1-mediated DNA cleavage sites, MJ-III-65 can accommodate different base pairs at the (-1), (+1), or (+2) position, with a preference for a cytosine at the (-1) position on the scissile strand. Another difference with CPTs is the activity of MJ-III-65 against CPT-resistant top1 enzymes, implying that the amino acid residue interactions with top1 are different for MJ-III-65 and CPTs. As with CPT, MJ-III-65 is inactive against vaccinia top1. This study shows the specific molecular interactions of MJ-III-65 with top1 and demonstrates that MJ-III-65 is a potentially useful top1 inhibitor that enhances and traps top1 cleavage sites not sensitive to CPTs. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/14612542/Differential_induction_of_topoisomerase_I_DNA_cleavage_complexes_by_the_indenoisoquinoline_MJ_III_65__NSC_706744__and_camptothecin:_base_sequence_analysis_and_activity_against_camptothecin_resistant_topoisomerases_I_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=14612542 DB - PRIME DP - Unbound Medicine ER -