Additional file 2 shows a table with characteristics and results of the included studies. The positive, negative and conflicting findings from these studies are summarized excellent validation in Table 1. Histopathological studies of the myocardium The histopathological effects of 5 FU were examined in two animal studies. In rat hearts, multifocal intersti tial hemorrhages, multifocal myofiber necrosis, inflam matory reactions including perivascular involvement, pericarditis, valvulitis and vascular changes, were found. The vascular changes included dilated vessels, rup tured vascular walls, extravasation of blood and micro thrombosis. In rabbits, a single high intravenous dose resulted in hemorrhagic infarction of the ventricle walls, proximal spasms of the coronary arteries and lethal out come for all rabbits within 1 day.

In contrast, repeated lower doses resulted in left ventricular hypertrophy due to reticular Inhibitors,Modulators,Libraries interstitial fibrosis with edema, concentric fibrous thickening of the intima of small distal coronary arteries and Inhibitors,Modulators,Libraries disseminated foci of necrotic myocardial cells. Whether the differences in histopathological effects were species specific, or due to different doses, is not clear. Histopathological studies of the arteries Four studies examined the histopathological ef fects of 5 FU on the arterial endothelium in rabbits. Scanning electron microscopy of the arteries showed ex tensive cytolysis, denudation of the underlying internal elastic lamina, platelet aggregation and fibrin formation. Areas of contracted vessel walls with contracted endothelial cells were present.

Cell detachment was frequently seen and endothelial cells presented with a range of morphologic features compatible with cytolysis. The endothelial damage was comparable in ar teries exposed to direct injection of 5 FU and arteries ex posed Inhibitors,Modulators,Libraries to 5 FU through systemic circulation. The endothelial changes were most pronounced on day 3 after 5 FU injections and had diminished Inhibitors,Modulators,Libraries on day 7 and day 14. Concomitant treatment with probucol, a lipid lowering drug with strong antioxidant properties, abrogated the ef fects of 5 FU on the endothelium, while concomitant treatment with dalteparin, a low molecular weight heparin, resulted in a somewhat different picture with endothelial damage on day 3, diminishing on day 7 but increasing again by day 14. Dalteparin prevented fibrin formation and to a lesser extent platelet aggregation.

Inhibitors,Modulators,Libraries Studies on cultured myocardial and endothelial cells In vitro treatment of H9c2 rat cardiomyocytes with 5 FU induced a time and dose dependent merely growth in hibition that was enhanced by levofolene. Apoptosis was more frequent in 5 FU and levofolene treated H9c2 cells compared with colon cancer cells, and cleavage of cas pase 3, an effector caspase in the apoptotic pathways, was increased in 5 FU treated H9c2 cells. Moreover, super oxide anion levels increased.