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

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 Hydroxyrubicin is a synthetic analog of doxorubicin in which the basic amino group at the C-3' has been replaced by a hydroxyl group in order to overcome recognition by the multidrug resistant (MDR) P-glycoprotein and limit cardiotoxicity. The present study shows that hydroxyrubicin 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 microM. 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 clonogenic assay, we observed that hydroxyrubicin was 20-fold more cytotoxic against the MDR KB-V1 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 1 hr in KB3.1 cells and rapidly eliminated from resistant KB-V1 cells. In contrast, hydroxyrubicin was rapidly eliminated from both sensitive KB3.1 and MDR-positive KB-V1 cells. Both drugs induced protein-linked DNA single-strand breaks (SSBs) in both KB3.1 and KB-V1 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-V1 cell lines after hydroxyrubicin removal while DNA breaks induced by doxorubicin disappeared very slowly in KB3.1 cells and rapidly in KB-V1 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.

• Authors: E Solary, Y H Ling, R Perez-Soler, W Priebe, Y Pommier
• Journal: International journal of cancer (Int J Cancer) Vol. 58 Issue 1 Pg. 85-94 (Jul 01 1994) ISSN: 0020-7136 [Print] United States
• PMID: 8014019 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Antineoplastic Agents
• DNA, Neoplasm
• Topoisomerase II Inhibitors
• Epirubicin
• 3'-deamino-3'-hydroxydoxorubicin
• Doxorubicin

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Agents (pharmacokinetics, pharmacology, toxicity)
• DNA Damage
• DNA, Neoplasm (drug effects, metabolism)
• Doxorubicin (analogs & derivatives, pharmacokinetics, pharmacology)
• Drug Resistance (physiology)
• Drug Screening Assays, Antitumor
• Epirubicin (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)
• Humans
• KB Cells
• Topoisomerase II Inhibitors