Title:Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
Volume: 16
Issue: 6
Author(s): Derek W. Edwardson, Rashmi Narendrula, Simon Chewchuk, Kyle Mispel-Beyer, Jonathan P.J. Mapletoft and Amadeo M. Parissenti
Affiliation:
Keywords:
Anthracyclines, anti-tumor effects, cardiotoxicity, deoxyaglycone, hydroxylation, metabolites, optimization, semi-quinone, therapeutic
index.
Abstract: Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized
within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects.
However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the
various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines,
or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug antitumor
efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments
both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction
(hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation
within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation
of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted
in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity.
The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains
unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.
