Elsevier

Biochemical Pharmacology

Volume 57, Issue 7, 1 April 1999, Pages 727-741
Biochemical Pharmacology

Commentaries
A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin

https://doi.org/10.1016/S0006-2952(98)00307-4Get rights and content

Abstract

The mechanisms responsible for the antiproliferative and cytotoxic effects of the anthracycline antibiotics doxorubicin (Adriamycin®) and daunorubicin (daunomycin) have been the subject of considerable controversy. This commentary addresses the potential role of DNA synthesis inhibition, free radical formation and lipid peroxidation, DNA binding and alkylation, DNA cross-linking, interference with DNA strand separation and helicase activity, direct membrane effects, and the initiation of DNA damage via the inhibition of topoisomerase II in the interaction of these drugs with the tumor cell. One premise underlying this analysis is that only studies utilizing drug concentrations that reflect the plasma levels in the patient after either bolus administration or continuous infusion are considered to reflect the basis for drug action in the clinic. The role of free radicals in anthracycline cardiotoxicity is also discussed.

Section snippets

Proposed mechanisms of drug action

To evaluate the mechanisms of drug action that may be relevant to the clinical effectiveness of these agents, it is necessary to establish the actual drug concentrations that are achieved and/or sustained in patients undergoing treatment. At doses for bolus administration varying between 15 and 90 mg/m2, the maximal initial plasma concentration detected was approximately 5 μM 96, 97, while the lowest reported concentration was approximately 0.3 μM [98]; generally, initial plasma concentrations

Summary

In summary, it appears that the multiple mechanisms of action that have been ascribed to the anthracyclines may be related to the utilization of different drug concentrations under varied experimental conditions. When cells are exposed to drug concentrations in the submicromolar range, induction of cell differentiation (with prolonged exposure) and interference with DNA unwinding/DNA strand separation and DNA helicase may be evident. At drug concentrations that reflect the peak plasma

Acknowledgements

This work was supported by Grant CA55815 from the National Institutes of Health/National Cancer Institute and United States Army Medical Research and Material Command Award DAMD 17–96-1–6167. The author would like to acknowledge Dr. James Doroshow for providing a copy of his review and to thank Dr. Nicholas Bachur and Dr. Karen Magnet for critical reading of the manuscript and helpful suggestions for revision.

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