The anti‐neoplastic drug 5‐fluorouracil produces echinocytosis and affects blood rheology

Baerlocher, Gabriela M.; Beer, Jürg H.; Owen, Gethin; Meiselman, H.J.; Reinhart, Walter H.

doi:10.1046/j.1365-2141.1997.4003212.x

Cited by 31 publications

(34 citation statements)

References 28 publications

(36 reference statements)

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“…In vitro studies of red blood cells (RBCs) incubated in 5-FU showed a dose-dependent, reversible transformation of RBCs into echinocytic shape [29,30], which resulted in impaired transit through small pores [29]. Also, alterations in membrane fluidity and RBC metabolism were observed [30-32]: potassium efflux increased [30], oxygen tension ( pO2 ) decreased [31,32], deoxy-hemoglobin levels increased [32], intracellular ATP levels declined and the intracellular 2,3-bisphosphoglycerate (2,3-BPG) concentration rose [31,32].…”

Section: Resultsmentioning

confidence: 99%

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

Polk

Vistisen

Vaage-Nilsen

et al. 2014

BMC Pharmacol Toxicol

207

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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Section: Resultsmentioning

confidence: 99%

“…Baerlocher et al [29] demonstrated a continuous decrease in blood viscosity with increasing 5-FU concentrations at low shear rates (the rate of change of velocity at which one layer of fluid passes over an adjacent layer) and increasing blood viscosity at high shear rates. 5-FU had no effect on plasma viscosity in this in vitro study [29].…”

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

207

150

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“…Several studies have demonstrated that RBCs may have a role in the transport of chemotherapeutic agents prominent among which are methotrexate (Lena et al, 1987) and 5-fluorouracil (Baerlocher et al, 1997). In this study, we set out to determine whether 667 COUMATE is sequestered into RBCs, as this may explain the high bioavailability of this agent despite its relatively high clearance rate.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats

et al. 2004

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Breast cancer is a major cause of mortality in Western countries and there is an urgent requirement for novel treatment strategies. The nonsteroidal sulphatase inhibitor 667 COUMATE inhibits hepatic steroid sulphatase and growth of oestrone sulphate stimulated tumours in the nitrosomethylurea-induced rat mammary model. Other compounds that contain an aryl sulphamate moiety, for example, oestrone-3-O-sulphamate, are sequestered into red blood cells (RBCs). The aims of this study were to determine the pharmacokinetics of 667 COUMATE and to investigate its sequestration into RBCs. We administered a single p.o. or i.v. dose (10 mg kg À1 ) of 667 COUMATE to rats and used a high-performance liquid chromatography method to measure the levels of the agent and its putative metabolites in plasma. 667 COUMATE had a bioavailability of 95% and could be detected in plasma for up to 8 h. Using two independent analytical methods, we demonstrated that 667 COUMATE is sequestered by RBCs both ex vivo and in vivo. Previous investigations have revealed that 667 COUMATE is rapidly degraded in plasma ex vivo. In this study, we demonstrate that 667 COUMATE is stabilised due to its sequestration into RBCs. In conclusion, the pharmacological efficacy and high oral bioavailability of 667 COUMATE may be partly a consequence of the ability of RBCs to both protect the agent from metabolic degradation and facilitate its transport to tissues. These data support the further clinical evaluation of this novel endocrine therapeutic agent.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Amraotkar¹,

Pachika²,

Grubb³

et al. 2016

Texas Heart Institute Journal

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Induced by 5-FluorouracilFulminant myocarditis is a rare but potentially life-threatening illness caused by 5-fluorouracil C hemotherapy regimens based on 5-fluorouracil (5-FU) are frequently administered in the treatment of gastrointestinal malignancies-especially colorectal carcinomas.1,2 Fulminant myocarditis is a rare but potentially life-threatening illness caused by 5-FU cardiotoxicity.3,4 Commonly presenting as chest pain, cardiac toxicity has manifestations that can include ischemic changes evident upon electrocardiography (ECG), and arrhythmias, myocardial infarction, heart failure, cardiogenic shock, and sudden death, with higher incidences in patients who have existing cardiac disease.5 Although salvage extracorporeal membrane oxygenation (ECMO) has been used successfully to treat various forms of cardiogenic shock, no data exist for the use of ECMO in the treatment of 5-FU-induced myocarditis. We report a case in which ECMO rescued a patient who was in cardiogenic shock resulting from 5-FU-associated fulminant myocarditis. Case ReportIn May 2014, a 49-year-old white man with newly diagnosed anal squamous cell carcinoma was being treated with combination therapy: radiotherapy, 5-FU, and mitomycin-C. At the start of chemotherapy, he had excellent exercise capacity and no history of cardiac disease to our knowledge. Hours after completing the first cycle of intravenous 5-FU treatment, the patient developed severe chest pain and presented at our emergency room.Upon arrival, the patient was alert, oriented, and hemodynamically stable, with a heart rate (HR) of 100 beats/min and a blood pressure (BP) of 100/70 mmHg. An ECG revealed diffuse ST-segment elevations (Fig. 1), and laboratory data included an elevated troponin I level (0.79 ng/mL). He was diagnosed with an ST-segmentelevation myocardial infarction and was transferred to the cardiac catheterization laboratory on an emergency basis.Coronary angiography revealed occlusion of the right coronary artery, which was well collateralized by the left anterior descending coronary artery (Fig. 2), and the Case Reports

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The anti‐neoplastic drug 5‐fluorouracil produces echinocytosis and affects blood rheology

Cited by 31 publications

References 28 publications

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

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

Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats

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

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