Hydroxyrubicin, a deaminated derivative of doxorubicin, inhibits mammalian DNA topoisomerase II and partially circumvents multidrug resistance

Eric Solary, Vi‐He ‐H Ling, Roman Perez‐Soler, Waldemar Priebe, Yves Pommier

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

In vivo effectiveness of doxorubicin remains restricted due to toxicity and drug resistance. Hydroxyrubicin is a synthetic analog of doxorubicin in which the basic amino group at the C‐3′ has been replaced by a hydroxyl group in order to overcome recognition by the multidrug resistant (MDR) P‐ghlcoprotein and limit cardiotoxicity. The present study shows that hydroxyribicin is a less potent intercalator than doxorubicin. Induction of topoisomerase II‐mediated DNA cleavage in the human C‐myc origin by the two drugs was similar, reaching a maximum at 0.5 μM. Results from the NCI Cell Screening program indicate a relatively good correlation between the cytotoxicity of the 2 drugs on 55 cell lines of various origins (r = 0.723). Using a donogenic assay, we observed that hydroxyrubicin was 20‐fold more cytotoxic against the MDR KB‐VI cell line than doxorubicin and was slightly more cytotoxic than doxorubicin in the sensitive KB3.1 cell line. Uptake studies showed that doxorubicin was retained up to I hr in KB3.1 cells and rapidly eliminated from resistant KB‐VI cells. In contrast, hydroxyrubicin was rapidly eliminated from both sensitive KB3.1 and MDR‐positive KB‐VI cells. Both drugs induced protein‐linked DNA single‐strand breaks (SSBs) in both KB3.I and KB‐VI cells, which is consistent with topoisomerase inhibition. However, the kinetics of DNA SSBs induced by both drugs was very different. DNA breaks disappeared quickly in both KB3.1 and KB‐VI cell lines after hydroxyrubicin removal while DNA breaks induced by doxorubicin disappeared very slowly in KB3.1 cells and rapidly in KB‐VI cells. We conclude that removal of the basic amino group at the C‐3′ of doxorubicin modifies drug transport and partially circumvents MDR without changing topoisomerase II inhibition when compared with doxorubicin. © 1994 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)85-94
Number of pages10
JournalInternational Journal of Cancer
Volume58
Issue number1
DOIs
StatePublished - Jul 1 1994
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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