However, it is unlikely that these alterations play an important role in the pathogen esis of 5 FU induced cardiotoxicity, as they were not confined to patients experiencing cardiotoxicity. The role of myocardial metabolism in 5 FU induced cardiotoxicity Animal studies of myocardial metabolism demonstrated depletion of Gemcitabine buy high energy phosphate compounds, citrate accumulation and increased oxygen consumption in the heart after pre treatment with 5 FU. Deple tion in high energy phosphate compounds can result from increased oxygen consumption leading to insuffi cient oxygen supply, increased anaerobic metabolism, or to metabolic derangements produced by 5 FU. The stable and increased myocardial blood flow observed in two studies suggests that insufficient blood and oxygen supply is not a contributing factor.

Inhibitors,Modulators,Libraries Instead, Suzuki et al. reported that the respiratory control rate of myo cardial mitochondria was significantly lower in rabbits treated with Inhibitors,Modulators,Libraries 5 FU compared with controls. Therefore, Millart et al. proposed that the increase in anaer obic metabolism and the increase in oxygen uptake could be due to reduced aerobic efficiency resulting from mitochondrial uncoupling. Uncoupling of the mitochon Inhibitors,Modulators,Libraries drial respiratory chain results in increased basal oxygen consumption and decreased ATP production. This theory should be further studied. The theory of oxidative stress The pathogenesis of 5 FU induced cardiotoxicity may involve oxidative stress, as increased levels of super oxide anion were demonstrated in H9c2 cells after 5 FU treatment.

Reactive oxygen species, like super oxide anions, are under normal physiological conditions cleared by antioxidant defense systems, such Inhibitors,Modulators,Libraries as so dium oxide dismutase and glutathione peroxidase. Superoxide anion is dismutated to hydrogen peroxide in a process catalyzed by SOD, and H2O2 is then eliminated by catalase or GSH Px. The activ ities of SOD and GSH Px were lowered in 5 FU treated guinea pigs demonstrating a reduced antioxidant cap acity. If not eliminated by cellular antioxidant systems, superoxide anions can generate the highly reactive and toxic hydroxyl radicals through the Haber Weiss reaction, which is catalyzed by iron. Increased ROS levels inside cells lead to oxidation of macromolecules, Inhibitors,Modulators,Libraries including lipids, nucleic acids, and proteins, thereby dis turbing cellular functions. MDA is a selleck chem frequently used marker of lipid peroxidation, and MDA levels were el evated in guinea pig hearts after 5 FU treatment, and slightly elevated in isolated rat hearts after 5 FU treatment. These findings indicate that some degree of oxidative stress and cellular damage takes place in animal hearts during 5 FU treatment. Like wise, Kinhult et al.