Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: A scanning microscopy evaluation

Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remai ns unclear but clinical data suggest that the endothelium of coronary arter ies may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogen ic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxici ty. In the present study we evaluate the role of antithrombotic treatment w ith dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endoth elium of 5-FU, dalteparin,and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endo thelium was seen in 5-FU-treated animals, often leading to intima disruptio n and denudation of underlying structures, with accompanying platelet accum ulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin Save lower scores on Day 3 because of l ess evidence of thrombotic events. However, the reversibility of the endoth elial damage was poorer in this group, as well as in the group that receive d dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5 -FU, secondary to its direct toxic effect on the vascular endothelium. Howe ver, the study indicates that dalteparin per se has a toxic effect on the e ndothelium that is different from that of 5-FU.