Adriamycin (doxorubicin) is a potent, broad-spectrum antineoplastic agent effective in treating a variety of cancers including both solid tumors and leukemias. However, the clinical value of this drug is limited by the development of a cumulative and irreversible dilated cardiomyopathy that is manifested as a progressive loss of ventricular performance in patients receiving repeated doses of the drug. Adriamycin cardiotoxicity is also characterized by a dose dependent decline in mitochondrial oxidative phosphorylation and a decrease in high-energy phosphate pools. Our hypothesis is that this results from a cumulative and irreversible modification of regulatory factors affecting the membrane permeability transition (MPT) pore by adriamycin. The enhanced sensitivity to induction of the MPT leads to a futile, energy-depleting cycling of calcium across the mitochondrial membrane, which we suggest accounts for the dose-dependent loss of respiratory efficiency and ATP synthesis in cardiac tissue from adriamycin-treated rats. We further suggest that these mitochondrial changes contribute to the progressive inability of cardiac tissue to tolerate metabolic stress, particularly those associated with induction of the MPT such as ischemia and reperfusion. Another critical element to this adriamycin-induced mitochondrial cardiomyopathy is its irreversibility, which constitutes a very serous problem clinically in treating cases of pediatric or recurrent neoplasias. The fact that the effect of adriamycin on mitochondrial bioenergetics outlasts the persistence of drug residues in tissues suggests that adriamycin, at sufficient doses, initiates an irrevocable sequence of events that continue beyond elimination of drug. Our hypothesis is that adriamycin interacts with mitochondrial membranes to initiate a series of reactions that lead to increased rates of free radical generation. Furthermore, we suggest that this is a self-perpetuating process that increases in magnitude despite the termination of drug treatment and elimination of drug residues from the tissues. Careful and rigorous testing of these jointly related hypotheses will provide valuable insight into the pathogenesis of adriamycin cardiomyopathy and is essential to the development of mechanism-based therapeutic strategies to minimize the dose-limiting effects of this clinically important anticancer chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058016-07
Application #
6726825
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Varghese, Jamie
Project Start
1997-09-15
Project End
2006-09-30
Budget Start
2004-04-01
Budget End
2006-09-30
Support Year
7
Fiscal Year
2004
Total Cost
$259,875
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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