The appearance of endothelium in small arteries after treatment with 5-fluorouracil. An electron microscopic study of late effects in rabbits.

Cardiotoxicity is an unexplained toxic manifestation of 5-fluorouracil (5-FU). Its possible mechanism could be a direct cytotoxic effect on the vascular endothelium. We have tested this hypothesis in an experimental study in rabbits, using scanning and transmission electron microscopic evaluation of endothelium in small arteries (the central artery of the ear). The perfusion fixation method at physiological pressure and temperature was used. Both local and systemic effects of 5-FU on endothelium were studied 1, 3, 7, 14 and 30 days after in vivo treatment with 5-FU. Fifteen rabbits were used and five additional animals served as controls. The following parameters were evaluated: vessel wall and endothelial cell contraction, cell oedema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation. For the description of each parameter, a scale of negative points (0.0-3.0) was used. We found severe cell damage with accompanying thrombus formation. The findings support the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on endothelium, is the pathophysiological mechanism behind 5-FU cardiotoxicity.