5-Fluorouracil induces arterial vasoconstrictions but does not increase angiotensin II levels

Abstract

Because the mechanisms of 5-Fluorouracil (5-FU) cardiotoxicity have not yet been completely identified, prophylactic options are not available. To our knowledge, there are no published data investigating the use of angiotensin converting enzyme (ACE) inhibitors for 5-Fluorouracil-associated cardiotoxicity. In this study, we aimed to evaluate the influence of 5-FU administration on the diameter of the brachial artery and the levels of angiotensin II. The patients were administered bolus 5-FU/leucovorin in the study group. Angiotensin II and troponin T assays, complete blood cell counts, hepatic and renal function tests were analyzed in five consecutive blood samples in the initiation, just after termination, and on 24, 48, and 72 h after termination of the regimen. Pre- and post-treatment angiotensin II and troponin T assays, complete blood cell counts, hepatic and renal function tests were also analyzed in the control group. Brachial arterial diameters were measured and recorded in all patients before and after the treatment. A total of 59 patients were included in this study. Thirty one out of 59 patients (52.5%) were in the 5-FU study group and the remaining 28 patients (47.5%) were in the control group. Basal and post-treatment brachial artery diameters in the 5-FU study group were 0.436 +/- 0.51 and 0.423 +/- 0.50 cm, respectively (P = 0.001). The corresponding values in the controls were 0.3954 +/- 0.50 and 0.3957 +/- 0.49 cm, basal and post-treatment, respectively (P = 0.979). Angiotensin II levels were not changed significantly at serial measurements (P = 0.496). Moreover, the corresponding measurements were not statistically different in both two groups treated with and without 5-FU (P = 0.372). The pathophysiology of 5-FU-induced cardiac toxicity has not yet been elucidated. In the present study, 5-FU-associated vasoconstriction was not dependent on angiotensin II levels, thus we suggest that the prophylactic administration of ACE inhibitors cannot prevent cardiotoxicity in these patients. The underlying mechanisms of cardiotoxicity related to 5-FU might be multifactorial; nevertheless, further prospective investigation for the toxic effects of fluoropyrimidines on the coronary endothelium and myocardium are needed.

Role of Urotensin-2 in 5-Fluorouracil-Related Arterial Vasoconstriction in Cancer Patients

“…The increases in these groups were significantly higher than that in the control group (p = 0.019). Although in our previous study [10] we were able to demonstrate constriction of the brachial artery diameter due to bolus 5-FU administration, in the present study brachial artery diameters did not significantly decreased in either group before and after 5-FU administration; only a very slight insignificant decrease was seen. The increase of UT-2 levels in the bolus and CI groups thus does not appear to be related to brachial artery diameter values; nevertheless, we consider that this slight decrease may indicate a possible relationship between 5-FU-related cardiac toxicity and UT-2 levels.…”

“…It is possible that, due to measurement technique or other uncertain issues, this vasoconstriction were not clearly identified. In our previous study [10], significant constriction in brachial artery diameters was shown with bolus 5-FU administration. In addition, 5-FU-related vasoconstriction was shown in 2 other studies [8,9].…”

“…One of our previous studies searched for a relationship between 5-FU-related cardiotoxicity and angiotensin II levels [10]. In that study, we evaluated the effect of 5-FU administration on the diameter of the brachial artery and the levels of angiotensin II.…”

“…In that study, we evaluated the effect of 5-FU administration on the diameter of the brachial artery and the levels of angiotensin II. We found that 5-FU-associated vasoconstriction was not dependent on angiotensin II levels, and suggested that the prophylactic administration of ACE inhibitors cannot prevent cardiotoxicity in these patients [10]. …”

5-fluorouracil induced cardiotoxicity: Review of the literature

“…Eskilsson et al [48] attempted to prevent vasospasm-induced 5-FU cardiotoxicity via preadministration of verapamil without significant clinical effect. Another study by Salepci et al [49] pursued prophylactic administration of ACE inhibitors for the prevention of 5-FU induced cardiomyopathy without effect. Another potentially promising preventive therapy is the pre-administration of a strong antioxidant like probucol, which has demonstrated effectiveness in the lab, but whose efficacy has yet to be confirmed in human subjects [19].…”