Effects of Probucol on Endothelial Damage by 5-Fluorouracil

Abstract

Cardiotoxicity is a serious side effect of cancer treatment with the commonly used drug 5-fluorouracil (5-FU). The pathophysiology of this is unclear. Experimental studies show a thrombogenic effect of 5-FU, secondary to a direct toxic effect on the endothelium, possibly mediated by radical generation. Probucol is a lipid-lowering drug with strong antioxidant properties. The aim of this study was to evaluate the possibility of using probucol treatment to protect against the toxicity of 5-FU on vascular endothelium of the central artery in the ears of rabbits. Five groups of rabbits were treated with 1) 5-FU, 2) saline, 3) probucol high-dose and saline, 4) probucol high-dose and 5-FU, 5) probucol low-dose and 5-FU. Damage to the arterial endothelium was evaluated by scanning electron microscopy. Damage to the endothelium in 5-FU + probucol-treated animals was minimal and comparable to that of the control group. Intima disruption or thrombus formation was seen with 5-FU only. The results of the study indicate that treatment with probucol prevents 5-FU-induced endothelial injury.

5-fluorouracil induced cardiotoxicity: Review of the literature

“…Both animal and human studies demonstrate a dose dependent vasospasm that ceases with cessation of drug administration [2,4]. Experimental evidence also supports a direct toxic effect of the 5-FU on the coronary endothelium [20] and a hypercoagulable state which together precipitate acute thrombotic events [3,19].…”

“…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]. Overall, most investigators suggest decrease in drug dosage as the most effective strategy [6,48].…”

“…Numerous mechanisms have been proposed (Table 3). Clinically significant coronary vasospasm causing myocardial ischemia is the most commonly suspected mechanism, occurring in 1.2-18% of cases, even in the absence of CAD [1,4,[17][18][19]. Both animal and human studies demonstrate a dose dependent vasospasm that ceases with cessation of drug administration [2,4].…”

Acquired factor VII deficiency following FOLFOX in a patient with colorectal cancer who was also DPD deficient

“…There have been changes in protein C, fibrinopeptide A, von Willebrand factor, and fibrin D-dimer reported following 5-FU therapy in vivo and in vitro [Kuzel et al 1990;Kinhult et al 2001]. We recently published a case report of a DPYD variant (Y186C) specific to individuals of African descent in a patient with life-threatening 5-FU toxicity [Kinhult et al 2003]. In the same patient, we observed factor VII (FVII) deficiency; a finding that we believe deserves further attention and discussion.…”

Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond

“…In addition, it determines endothelial damage with a ROS-dependent mechanism [72]. Although the inhibition of EC proliferation during tumor angiogenesis is an important strategy for tumor starvation, thus blocking their progression, systemic inhibition of VEGF also hampers endothelial cell homeostasis leading to atherogenesis and arterial thromboembolic events, which often results in myocardial infarction, cerebrovascular insults, and peripheral or mesenteric ischemia [73][74][75].…”