Adriamycin (doxorubicin) and the related anthracycline antibiotics are potent, broad-spectrum, antineoplastic agents, but their therapeutic usefulness is limited by severe cardiotoxicity. The proposed research will test the hypothesis that adriamycin interacts with cardiolipin (diphosphatidylglycerol), a unique mitonchondrial phospholipid, inducing peroxidation of the lipid and interfering with one or more cardiolipin-dependent processes, so as ultimately to disrupt cellular homeostasis. Complementary studies of unilamellar liposomes and isolated rat heart mitochondria will be used to address four specific aims: (1) Identification of the mitochondrial process(es) mediated by cardiolipin and determination of their sensitivity to adriamycin. Experiments will focus on Ca2+ transport, phosphate (Pi) transport, and electron transport mediated by defined regions of the respiratory chain. (2) Estimation of the effect of lipid, particularly cardiolipin, peroxidation on cardiolipin function in the liposome model and on development in vitro and in vivo of adriamycin effects on mitochondria. (3) Identification of the factor(s) that render cardiac tissue especially susceptible to the toxic effects of the anthracyclines. Heart and liver will be compared in terms of the extent of cardiolipin peroxidation induced by adriamycin and the magnitude and adriamycin-sensitivity of cardiolipin-mediated processes. (4) Comparison of the effects on cardiolipin function and cardiolipin peroxidation of adriamycin analogs differing in cardiotoxicity. The overall goal is a sufficiently detailed description of the biochemistry of adriamycin cardiotoxicity to permit the design of efficacious protective strategies. However, a broadened understanding of the Ca2+ transport mechanisms of heart mitochondria would also contribute to the successful management of conditions, such as ischemia, prolonged hypoxia, and some cardiomyopathies, in which cardiac damage results from failure of intracellular Ca2+ homeostasis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Physical Biochemistry Study Section (PB)
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University of Maryland Baltimore
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Brown, P C; Sokolove, P M; McCann, D J et al. (1996) Induction of a permeability transition in rat kidney mitochondria by pentachlorobutadienyl cysteine: a beta-lyase-independent process. Arch Biochem Biophys 331:225-31
Sokolove, P M (1994) Interactions of adriamycin aglycones with mitochondria may mediate adriamycin cardiotoxicity. Int J Biochem 26:1341-50
Sokolove, P M; Kester, M B; Haynes, J (1993) Interaction of adriamycin aglycones with isolated mitochondria. Effect of selenium deficiency. Biochem Pharmacol 46:691-7
Sokolove, P M (1991) Oxidation of mitochondrial pyridine nucleotides by aglycone derivatives of adriamycin. Arch Biochem Biophys 284:292-7
Sokolove, P M; Kester, M B; Westphal, P A (1991) Duramycin effects on the structure and function of heart mitochondria. II. Energy conversion reactions. Arch Biochem Biophys 287:180-5
Sokolove, P M (1990) Inhibition by cyclosporin A and butylated hydroxytoluene of the inner mitochondrial membrane permeability transition induced by adriamycin aglycones. Biochem Pharmacol 40:2733-6
Kester, M B; Sokolove, P M (1990) The effect of adriamycin and duramycin on calcium translocation in liposome systems modeled on the inner mitochondrial membrane. Arch Biochem Biophys 280:405-11
Kester, M B; Sokolove, P M (1989) Calcium translocation in liposome systems modeled on the mitochondrial inner membrane. Biochim Biophys Acta 980:127-33
Sokolove, P M; Westphal, P A; Kester, M B et al. (1989) Duramycin effects on the structure and function of heart mitochondria. I. Structural alterations and changes in membrane permeability. Biochim Biophys Acta 983:15-22
Sokolove, P M; Kester, M B (1989) Quantitation of Ca2+ uptake by Arsenazo III-loaded liposomes. Anal Biochem 177:402-6

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