Hydroxyrubicin, a deaminated derivative of doxorubicin, inhibits mammalian DNA topoisomerase II and partially circumvents multidrug resistance.
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 Hydroxyrubicin is a synthetic analog of doxorubicin in which the basic amino group at the C-3' has been replaced by a hydroxyl group in order to overcome recognition by the multidrug resistant (MDR) P-glycoprotein and limit cardiotoxicity.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.
Solary
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Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Ling
Y H
YH
Perez-Soler
R
R
Priebe
W
W
Pommier
Y
Y
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D015251:Epirubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007624:KB Cells; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D059005:Topoisomerase II Inhibitors; D015251:Epirubicin; C042907:3'-deamino-3'-hydroxydoxorubicin; D004317:Doxorubicin