31P-topical nuclear magnetic resonance (31P-TMR) studies of cardiotoxic effects of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR).

Tamatsu, Hirokuni; Nakazawa, Makoto; Imai, Shoichi; Watari, Hiroshi

doi:10.1254/jjp.34.375

Cited by 23 publications

(13 citation statements)

References 5 publications

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“…An evaluation of the statistical significance of the change in the mean phosphocreatine level reached for each dose, as compared to the mean phosphocreatine level in control animals, showed that the drug-induced effects are statistically significant (P < 0.5% at 10 mg/kg; P < 0.1% at 20 and 25 mg/kg). Effects on cardiac phosphocreatine of a similar magnitude as those described here have been reported by Tamatsu et al [27] upon administration of single, high doses of 5-fluorouracil to guinea pigs, as measured by 31p topical NMR.…”

Section: Acute Effectssupporting

confidence: 87%

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

Nicolay¹,

Aue

Seelig

et al. 1987

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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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.

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Section: Acute Effectssupporting

confidence: 87%

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

Nicolay¹,

Aue

Seelig

et al. 1987

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…2, recorded at a depth of 4 cm in the normal heart, shows a substantial decrease in all resonances. The peak discernible at about 6 ppm might be assigned to 2,3-bisphosphoglycerate in blood (9,10,12,13,22) occupying the left ventricle at this slice level (Fig. iD) and is unresolved perhaps because of blood flow effects (22) or a poor signal-to-noise ratio.…”

Section: Resultsmentioning

confidence: 96%

“…In situ studies have been attempted in larger-bore systems using surgically implanted NMR coils enclosing the hearts of open-chested or chronically implanted animals (9-11) or using catheter NMR coils inserted through a peripheral blood vessel (12). Surface coils positioned externally on the chest have yielded 31P spectra from guinea pig hearts when combined with the topical magnetic resonance technique for spatial localization and surgical removal of surface muscle tissue (13). Several other spectral localization schemes have been proposed (14)(15)(16) but not applied to the heart.…”

mentioning

confidence: 99%

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Noninvasive detection and monitoring of regional myocardial ischemia in situ using depth-resolved 31P NMR spectroscopy.

Bottomley¹,

Herfkens²,

Smith³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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Phosphorus (31P) NMR spectra showing the relative concentrations of phosphocreatine, ATP, and Pi were recorded noninvasively from localized regions in the left ventricles of dog hearts in situ by using depth-resolved surfacecoil spectroscopy at 1.5 T. Proton (1H) NMR surface-coil imaging was used to position 31P NMR coils and to determine the location of depth-resolved volumes immediately prior to 31P examination. Occlusion of the left anterior descending coronary artery produced regional ischemia detected as changes in the ratios of phosphocreatine, ATP, and Pi and by changes in the pH measured from the spectra. Spectral changes were not typically observed in regions adjacent to ischemic myocardium. Reperfusion produced some recovery, and ventricular fibrillation resulted in deterioration in high-energy metabolites. The location and size of ischemic tissue was measured by singlephoton-emission computed tomography (SPECT) and gammaray counting or by staining excised hearts. The technique should permit the long-term noninvasive monitoring of the metabolic response of the heart to pathologic processes and allow assessment of interventions. NMR spectrum is a profile of the relative concentrations of the high-energy phosphate metabolites phosphocreatine (PCr) and ATP as well as inorganic phosphate, Pi (1-6). Such spectra are responsive to changes in myocardial metabolism as early as 90 s after the onset of ischemia (3). To date, applications of 31P NMR spectroscopy to heart metabolism have proved invasive because of (i) the difficulty of achieving adequate spatial localization of the 31p signal to the heart, and (ii) the small magnet apertures of available

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“…Studies of myocardial metabolism in guinea pigs showed that 5-FU induced a decrease in myocardial high energy phosphate levels [12,36,37] and accumulation of citrate in the myocardium [12] reflecting increased anaerobic metabolism. These changes were associated with electrocardiographic (ECG) changes suggestive of myocardial ischemia occurring around 3 hours after intravenous administration of 5-FU [12].…”

Section: Resultsmentioning

confidence: 99%

A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity

Polk

Vistisen

Vaage-Nilsen

et al. 2014

BMC Pharmacol Toxicol

214

150

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BackgroundCardiotoxicity is a serious side effect to treatment with 5-fluorouracil (5-FU), but the underlying mechanisms are not fully understood. The objective of this systematic review was to evaluate the pathophysiology of 5-FU- induced cardiotoxicity.MethodsWe systematically searched PubMed for articles in English using the search terms: 5-FU OR 5-fluorouracil OR capecitabine AND cardiotoxicity. Papers evaluating the pathophysiology of this cardiotoxicity were included.ResultsWe identified 27 articles of 26 studies concerning the pathophysiology of 5-FU-induced cardiotoxicity. The studies demonstrated 5-FU-induced: hemorrhagic infarction, interstitial fibrosis and inflammatory reaction in the myocardium; damage of the arterial endothelium followed by platelet aggregation; increased myocardial energy metabolism and depletion of high energy phosphate compounds; increased superoxide anion levels and a reduced antioxidant capacity; vasoconstriction of arteries; changes in red blood cell (RBC) structure, function and metabolism; alterations in plasma levels of substances involved in coagulation and fibrinolysis and increased endothelin-1 levels and N-terminal-pro brain natriuretic peptide levels. Based on these findings the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia.ConclusionsThere is no evidence for a single mechanism responsible for 5-FU-induced cardiotoxicity, and the underlying mechanisms might be multifactorial. Further research is needed to elucidate the pathogenesis of this side effect.

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31P-topical nuclear magnetic resonance (31P-TMR) studies of cardiotoxic effects of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR).

Cited by 23 publications

References 5 publications

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

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

Noninvasive detection and monitoring of regional myocardial ischemia in situ using depth-resolved 31P NMR spectroscopy.

A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity

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