Cardiac lesions induced by 5-fluorouracil in the rabbit

Abstract

<jats:p> Cardiotoxicity is a rare, but well-recognized complication of treatments with the anti-cancer drug 5-fluorouracil (5FU). The underlying mechanism, however, is not fully elucidated. A spasm of the coronary arteries is often considered to be the leading cause of myocardial ischemia and decreased contractility associated with 5FU. As spasm cannot account for all reported adverse cardiac effects, the present study was undertaken to search for alternative mechanisms. Groups of six rabbits were given either a single intravenous dose of 50 mg/kg 5FU or four intravenous doses of 15 mg/kg 5FU at 7-day intervals. A third group served as control. The heart was removed shortly after death or scheduled sacrifice of the animals, to perform macroscopic and microscopic examinations of the heart and to evidence apoptosis by the TUNEL method. Following a single dose of 50 mg/kg 5FU, all animals rapidly developed a massive hemorrhagic myocardial infarct with spasms of the proximal coronary arteries. Repeated infusions of 15 mg/kg 5FU induced left ventricular hypertrophy, foci of myocardial necrosis, thickening of intra-myocardial arterioles, and disseminated apoptosis in myocardial cells of the epicardium, as well as endothelial cells of the distal coronary arteries. These results indicate that a spasm of the coronary arteries is not the only mechanism of 5FU cardiotoxicity, and that apoptosis of myocardial and endothelial cells can result in inflammatory lesions mimicking toxic myocarditis. </jats:p>

5-fluorouracil induced cardiotoxicity: Review of the literature

“…A single large dose demonstrated massive hemorrhagic MI associated with coronary spasm, while repeated lower dose infusions resulted in left ventricular hypertrophy with necrosis, thickening of arteries, and apoptosis of endothelial cells. This same study also demonstrated that 5-FU can cause a diffuse myocarditis instead of vasospasm with subendocardial sparing along with inflammation [29]. Another case report utilizing ventricular biopsy demonstrated sarcoplasmic reticulum dilatation, similar to doxorubicin-associated cardiomyopathy [30].…”

“…De Forni et al [12] suggested the possibility of a direct drug (or drug-metabolite) toxic action on the myocardium, particularly given evidence that there is global systolic dysfunction, which does not correspond to any individual coronary artery territory. Another animal study demonstrated different toxic effects depending on the dose and frequency of drug administration [29]. A single large dose demonstrated massive hemorrhagic MI associated with coronary spasm, while repeated lower dose infusions resulted in left ventricular hypertrophy with necrosis, thickening of arteries, and apoptosis of endothelial cells.…”

Modification of Post-Myocardial Infarction Granulocyte-Colony Stimulating Factor Therapy With Myelosuppressives

“…Five-fluorouracil gives rise to spasms of the coronary arteries, rhythm disturbance and myocardial and endothelial inflammation underlying their apoptosis at an acute phase of treatment, although at a higher dosage than in the present study. 27 Similarly, a higher dose of cyclophosphamide is toxic for endothelium and myocytes, and causes interstitial hemorrhage and edema. 28 Although the dosage of the present experimental setting did not lead to any severe adverse effects, we need to monitor hemodynamics following treatment of the agents in the clinical setting closely.…”

Rapid Extracorporeal Membrane Oxygenation Overcomes Fulminant Myocarditis Induced by 5‑Fluorouracil

“…2,5 The exact mechanism is currently unclear, but the authors of a systematic review 5 have proposed multifactorial underlying causes, including endothelium-dependent and -independent pathways, direct myocardial damage from cytotoxic effects, induction of apoptosis, rheological side effects, and the production, during drug storage, of cardiotoxic metabolite precursors (for example, fluoro acetate). [6][7][8][9][10][11][12] Animal models of 5-FU cardiotoxicity have manifested apoptosis of myocytes, endothelial cells, or both, which gives rise to clinical presentations similar to that of myocarditis. 12 The toxicity of 5-FU is dependent on the duration of treatment, on the rate of administration, or both; continuous infusions have higher incidences than do bolus regimens.…”

“…[6][7][8][9][10][11][12] Animal models of 5-FU cardiotoxicity have manifested apoptosis of myocytes, endothelial cells, or both, which gives rise to clinical presentations similar to that of myocarditis. 12 The toxicity of 5-FU is dependent on the duration of treatment, on the rate of administration, or both; continuous infusions have higher incidences than do bolus regimens. 13,14 Pre-existing cardiac disorders are risk factors for future 5-FU cardiotoxicity.…”