THE INFLUENCE OF 5-FLUOROURACIL ON THE ENDOTHELIUM IN SMALL ARTERIES - AN ELECTRON-MICROSCOPIC STUDY IN RABBITS

5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU indu ced cardiotoxicity is a still relatively unknown side-effect of this d rug. This phenomenon could be due to a direct cytotoxic effect on the endothelial cells. We tested this hypothesis in an experimental study in rabbits, by scanning or transmission electron microscopic evaluatio n of endothelium in small arteries (the central artery of the ear) aft er in vivo treatment with 5-FU. Both local and systemic effects of 5-F U on endothelium were studied 15, 30, 60 and 120 minutes after intra-a rterial or intraperitoneal treatment. Perfusion fixation at physiologi cal pressure and temperature was used in order to minimize damage to t he endothelium during the preparation procedure. Eighteen rabbits weig hing 2.5-3.0 kg were used, and 6 animals served as controls. The follo wing parameters were evaluated: vessel wall and endothelial cell contr action, cell edema, cytolysis, occurrence of denuded areas, platelet a dhesion/aggregation and fibrin formation. For the description of each parameter a scale of negative points was used. Irreversible cell damag e was observed in 5-FU treated animals: disruption of the endothelial sheet and patchy exposure of the subendothelium, sometimes as a focus for thrombus formation. Our findings support the hypothesis that the t hrombogenic effect of 5-FU secondary to its direct cytotoxic effect on endothelium might be one of the pathophysiological mechanisms behind 5-FU induced cardiotoxicity.