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

Abstract

The anti-neoplastic agent 5-fluorouracil (5-FU) in high therapeutic doses can induce angina pectoris and myocardial infarction. The pathophysiological mechanism of this side-effect has not yet been elucidated. We analysed the influence of 5-FU on blood rheology in vitro. Whole blood, blood cell suspensions and plasma were incubated with increasing concentrations of 5-FU (final concentrations 0, 0.08, 0.4, 2, 10 and 25 mg/ml 5-FU) at 37 degrees C. Erythrocyte morphology was analysed after fixation with glutaraldehyde. Viscosity was measured at high and low shear rates (94 and 0.1 s[-1]). Erythrocyte aggregation and the cell transit times of erythrocytes through 5 microm pores and polymorphonuclear leucocytes through 8 microm pores were determined. 5-FU induced a dose-dependent formation of echinocytes within minutes and was reversible upon removal of 5-FU, which reflected a preferential intercalation of the drug in the outer hemileaflet of the cell membrane. High shear blood viscosity was increased at the highest 5-FU concentration (148 +/- 12%), and at low shear rate a dose-dependent decrease was found (0 mg/ml: 100%, 0.08 mg/ml: 87 +/- 10%, 0.4 mg/ml: 80 +/- 19%, 2 mg/ml: 70 +/- 15%, 10 mg/ml: 40 +/- 19%, 25 mg/ml: 33 +/- 5%). Erythrocyte aggregation was decreased by the 5-FU-induced echinocytosis. The transit time of erythrocytes through narrow pores was increased in a dose-dependent manner by 5-FU, whereas the transit time of polymorphonuclear leucocytes was initially decreased at 10 mg/ml and returned to control after 60 min incubation. We conclude that 5-FU interacts with the cell membrane, induces echinocytosis and vesiculation and affects blood rheology in several ways which may contribute to cardiovascular complications.