Effects of the anti-cancer drug adriamycin on the energy metabolism of rat heart as measured by in vivo 31P-NMR and implications for adriamycin-induced cardiotoxicity

Abstract

In vivo 31p-NMR was used to measure the effects of the anti-tumor drug adriamycin on the energy metabolism of rat heart. The exclusive acquisition of NMR signal from cardiac muscle was assured by positioning a solenoidal radio-frequency NMR coil around the heart. Appropriate control experiments verified that 31p-NMR spectra solely originated from this organ. Acute effects occurring shortly after adriamycin administration are expressed in 31p spectra as a dose-dependent decline in the cardiac levels of phosphocreatine, after which stabilization at a new steady-state level occurs. These acute effects of a single dose are complete in 30-60 min and no significant further changes take place within 150 min after drug introduction. Longer-term effects of single high doses and of multiple lower doses were measured up to a week after the initiation of treatment. It seemed that at a total dose of 20 mg/kg, drug-induced interference with cardiac energy metabolism was more pronounced than at the same dose in the acute phase. These 31p-NMR data demonstrate that adriamycin treatment is accompanied by a decrease of the cardiac phosphocreatine/ATP ratio which might be an expression of the well-established cardiotoxicity of the drug.

Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply

“…However, the lower total CK activity together with solubilized and dimerized sMtCK could certainly contribute to a diminished high-energy phosphate level. For example, 1-h perfusion of rat hearts with 10 M DXR was estimated to cause an about 20% decrease in both ATP and PCr levels (33,40), and a similar decrease was observed in animals upon single DXR injection (29). In turn, it seems plausible that decreased AMPK signaling can be an important factor mediating acute cardiac dysfunction, especially under hypoxic conditions due to strongly decreasing coronary flow, as it was the case at 20 M DXR.…”

“…An important manifestation of DXR cardiotoxicity is an impaired cardiac high-energy phosphate metabolism. Acute and chronic consequences of DXR administration include compromised mitochondrial functions, such as respiration and generation of high-energy phosphates (30) and lowered phosphocreatine-to-creatine (PCr/Cr), PCr-to-ATP (PCr/ATP), and ATP-to-ADP (ATP/ADP) ratios as well as compromised calcium homeostasis (8,29,31). However, the involved molecular mechanisms are not yet entirely understood.…”

Creatine Kinase-Overexpression Improves Myocardial Energetics, Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity

“…In isolated myocytes, DOX reduces high-energy phosphates by 30% or more in many studies [2]. In isolated perfused hearts DOX lowers cardiac PCr and ATP acutely [22,40] and, in hearts previously administered DOX on a chronic basis, the high-energy phosphate reductions were even larger [19]. In vivo cardiac PCr/ATP declines after chronic DOX administration and the decline precedes contractile abnormalities and predicts eventual mechanical dysfunction [27].…”

The interaction of Fe(III), adriamycin and daunomycin with nucleotides and DNA and their effects on cell growth of fibroblasts (NIH-3T3)

“…The usefulness of these drugs in chemotherapy is, however, tempered by toxic side effects which include conventional toxicities and a dose-limiting cumulative cardiotoxicity (Young et al 1981). Various models on the mode of cytotoxicity of anthracyclines have been proposed, including change of membrane properties, in particular of heart mitochondria (Goormaghtigh et al 1987, Nicolay et al 1987, GarnierSuillerot & Gattegno 1988, Bradmante et al 1989), binding to DNA by intercalation (Chaires et al 1989, Wang et al 1987, Skorobogaty et al 1988, Ragg et al 1988, Gresh et al 1989), formation of a ternary anthraeycline-DNA topoisomerase II cleavage complex (Fritzsche & W~ihnert 1987), inhibition of the RNA polymerase-catalysed synthesis of RNA (Kriebardis et al 1987), formation of reactive anthracycline degradation products (Olson et al 1988) and the formation of reactive radicals by metabolic processes tDoroshow 1983, Ashnagar et al 1984, Abdella & Fisher 1985. It has been experimentally difficult to decipher which of these various biochemical events are responsible for the cyto-and cardiotoxicity of ADM and DN.…”