Pathophysiology of 5-fluorouracil induced cardiotoxicity : a clinical and experimental study

Abstract: This thesis concerns the pathophysiology of 5-fluorouracil (5-FU) induced cardiotoxicity. The aim of the clinical studies was to determine whether hemorheological factors might explain 5-FU cardiotoxicity (I) and if the syndrome was associated with free radical (FR) generation and lipid peroxidation (II). Changes in blood and plasma viscosity, fibrinogen, hematocrit, and thiobarbituric acid-reactive substances (TBARS) were studied in patients with esophageal or head and neck carcinoma during treatment with 5-FU. The study showed a decrease in blood and plasma viscosity, probably caused by a decrease in fibrinogen. Study of TBARS did not support the hypothesis that FRs could be involved in the cardiotoxicity of 5-FU. In the experimental studies in rabbits (III,IV) we examined the early and late, local and systemic effect of 5-FU on endothelium, using scanning and transmission electron microscopic evaluation of small arteries, after in vivo treatment with 5-FU. Perfusion fixation was used. The following parameters were evaluated: vessel wall and endothelial cell (EC) contraction, EC edema, cytolysis, denuded areas, platelet accumulation, fibrin formation. The studies showed severe damage to ECs with accompanying thrombus formation, supporting the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on the endothelium is the pathophysiological mechanism of 5-FU cardiotoxicity. The influence of 5-FU on endothelial cell lines in a cell culture model was studied with regard to DNA synthesis, cell death and release of prostacyclin (V). Methotrexate (MTX), an antimetabolite without cardiotoxic properties, was tested in the same way. (3H)thymidine incorporation, total cellular protein, loss of (3H)thymidine from prelabelled cells, 6-keto-prostaglandin F1' were measured. DNA synthesis decreased significantly and the release of prostacyclin by ECs increased significantly when incubated with 5-FU; this effect was not seen for MTX. The study indicate specific susceptibility of benign EC for 5-FU.