Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Relationship between Lethal Effects and Topoisomerase II-Mediated Double-Stranded DNA Breaks Produced by Anthracyclines with Different Sequence Specificity

Monica Binaschi, Giovanni Capranico, Laura Dal Bo and Franco Zunino
Molecular Pharmacology June 1997, 51 (6) 1053-1059; DOI: https://doi.org/10.1124/mol.51.6.1053
Monica Binaschi
Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giovanni Capranico
Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura Dal Bo
Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Franco Zunino
Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

The role of the site selectivity of topoisomerase II poisoning in the cytotoxic activity of anthracyclines has not been established. In this article, we have thus studied the levels and persistence of double-stranded DNA breaks (DSB) along with the cytotoxic activity in human leukemic HL60 cells of seven anthracyclines, including doxorubicin, daunorubicin, and idarubicin, as well as sugar-modified analogues characterized by an altered sequence specificity. Epimerization at the 3′ position of the sugar moiety markedly affected the biological activity; indeed, a dramatic reduction of drug effects was evident for 3′-deamino-3′-epi-hydroxy-4′-deoxy-4′-amino-daunorubicin. The studied analogues could be gathered into three groups based on the DSB/cytotoxicity ratio. At equitoxic concentrations: (a) parent drugs and 3′-deamino-3′-epi-hydroxy-4′-deoxy-4′-amino-daunorubicin endowed with the same sequence specificity stimulated low DSB levels; (b) 3′-epi-daunorubicin and 3′-deamino-4′-deoxy-4′-epi-amino-idarubicin, which have a different sequence specificity, and teniposide (a structurally unrelated poison) stimulated higher amounts of DSB; and (c) 4-demethoxy-3′-deamino-3′-hydroxy-4′-epi-doxorubicin stimulated the highest DSB levels. For the last agent, a faster rate of cleavage resealing, which is consistent with a reduced DNA binding affinity, could account for the increased DSB/cytotoxicity ratio compared with parent drugs. However, for other analogues, the observed differences in DSB persistence/resealing could not completely explain the different DSB/cytotoxicity ratios. The results thus suggest that the cytotoxic potency of anthracyclines may be the result of an interplay of the level, the persistence, and the genomic localization of topoisomerase II-mediated DNA cleavage.

Footnotes

    • Received December 20, 1996.
    • Accepted March 4, 1997.
  • Send reprint requests to: Giovanni Capranico, Istituto Nazionale Tumori, 20133 Milan, Italy. E-mail:capranico{at}icil64.cilea.it

  • This work was supported in part by Associazione Italiana per la Ricerca sul Cancro, Milan, Italy, and by Consiglio Nazionale delle Ricerche, Progetto Finalizzato Applicazioni Cliniche della Ricerca Oncologica, Rome, Italy.

  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 51 (6)
Molecular Pharmacology
Vol. 51, Issue 6
1 Jun 1997
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Relationship between Lethal Effects and Topoisomerase II-Mediated Double-Stranded DNA Breaks Produced by Anthracyclines with Different Sequence Specificity
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Relationship between Lethal Effects and Topoisomerase II-Mediated Double-Stranded DNA Breaks Produced by Anthracyclines with Different Sequence Specificity

Monica Binaschi, Giovanni Capranico, Laura Dal Bo and Franco Zunino
Molecular Pharmacology June 1, 1997, 51 (6) 1053-1059; DOI: https://doi.org/10.1124/mol.51.6.1053

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Relationship between Lethal Effects and Topoisomerase II-Mediated Double-Stranded DNA Breaks Produced by Anthracyclines with Different Sequence Specificity

Monica Binaschi, Giovanni Capranico, Laura Dal Bo and Franco Zunino
Molecular Pharmacology June 1, 1997, 51 (6) 1053-1059; DOI: https://doi.org/10.1124/mol.51.6.1053
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Fatty Acid Amide Hydrolase in Cisplatin Nephrotoxicity
  • Use-Dependent Relief of A-887826 Inhibition
  • Benzbromarone Relaxes Airway Smooth Muscle via BK Activation
Show more Article

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics