Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

Cardiac troponins following repeated administration of an iron chelator--salicylaldehyde isonicotinoyl hydrazone (SIH)--in rabbits

Both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are considered to be reliable biomarkers with sufficient sensitivity and specificity for cardiac injury in the majority of laboratory animals. The aim of our study was to compare the diagnostic performance of cTnT and cTnI in three groups of rabbits: 1) control (saline 1 ml/kg i.v.); 2) Salicylaldehyde Isonicotinoyl Hydrazone--SIH (50 mg/kg, once weekly, i.p.; partially dissolved in 10% Cremophor solution); 3) 10% Cremophor solution in water (2 ml/kg i.v.). The drugs were given once a week, 10 administrations. The concentration of cTnT was measured using Elecsys Troponin T STAT Immunoassay (Roche). The concentration of cTnI was measured using AxSYM Troponin I (Abbott). The linear regression model was applied to see if there is a dependence between cTnT and cTnI. The coefficient of determination was not acceptable in all groups. The highest value of R2 was found in the control group (R2 = 0.424). We may conclude that in rabbits meaningful dependence between cTnT and cTnI was not found. According to our long-term experiences cTnT seems to be more suitable cardiomarker in rabbits in comparison with cTnI where the data are characterized by the large scatter.     

Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum

Background  

Combination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum.     

Comparative study of chronic toxic effects of daunorubicin and doxorubicin in rabbits

This study compares the chronic toxicity of two anthracyclines--daunorubicin and doxorubicin, commonly used for induction of anthracycline cardiomyopathy in the rabbit model. Such a comparative study has not been published until now. Both drugs were administered intravenously to male Chinchilla rabbits in doses at 3 mg/kg (50 mg/m2) once weekly for 10 weeks. Selected biochemical, haematological and cardiovascular parameters and body weights were regularly monitored; additionally, a histological evaluation of heart, kidney and liver was performed at the end of the experiment. In the daunorubicin group, there were marked signs of the progressive development of heart failure, like the significant increases of the pre-ejection period/left ventricular ejection time index values (up to 134%)--and histological changes within the myocardium were also observed. On the other hand, the 10-week doxorubicin administration did not cause these changes that are typical for heart injury. Haematotoxicity, manifested particularly by aplastic anaemia, was apparent in both the experimental groups. Significant body weight loss (by 45.2%) and high premature mortality (100% versus 36.4%) reflected a greater general toxicity, especially nephrotoxicity of doxorubicin in comparison with daunorubicin. Further studies are necessary to find a possible explanation for these findings.     

The fate of iron in the organism and its regulatory pathways

Iron is an essential element involved in many life-necessary processes. Interestingly, in mammals there is no active excretion mechanism for iron. Therefore iron kinetics has to be meticulously regulated. The most important step for regulation of iron kinetics is absorption. The absorption takes place in small intestine and it is implicated that it requires several proteins. Iron is then released from enterocytes into the circulation and delivered to the cells. Iron movement inside the cell is only partially elucidated and its traffic to mitochondia is not known. Surprisingly, the regulation of various proteins related to iron kinetics and energy metabolism at the molecular level is better described. On contrary, the complex control of iron absorption cannot be fully explicated with present knowledge.     

Endothelins and sarafotoxins: peptides of similar structure and different function

Endothelins are endogenous vasoactive peptides that are considered among the most potent vasoconstrictor substances known. In addition to their vascular effects, endothelins and their receptors have been shown to be present in many organs and share plenty physiological and pathophysiological functions. Sarafotoxins are natural substances from the venom of snakes genus Atractaspis, structurally and pharmacologically near to endothelins. The current minireview focuses on the chemical and molecular aspects of endothelins and sarafotoxins, and their receptors in physiological and pathophysiological processes.     

Wolman disease and cholesterol ester storage disease in adults. New means of study and diagnosis

Two clinical forms of lysosomal storage of neutral lipids with deficiency of acid lipase are known: the severe infantile form is called Wolman disease, whereas the more benign adult form is called "polycorie cholesterolique de l'adulte" or cholesteryl ester storage disease (CESD). We have developed several new tools for the study of hereditary enzymopathies and we report here their use in the study of genetic defects in lysosomal acid lipase. Lymphoid cell lines established by Epstein-Barr Virus transformation represent a new experimental model system in culture. The validity of such cell lines is demonstrated from the triple point of view of enzymology, metabolism and morphology (microscopic studies). Those lines are characterized by the deficiency in acid lipase whereas other lipases and carboxylesterases are not deficient. The study of lipid composition demonstrated the accumulation of neutral lipids (cholesterylesters and triglycerides). The use of fluorescent lipids for enzymatic studies and for diagnosing acid lipase deficiencies is reported and the reliability of these new substrates is demonstrated by comparison with currently used natural or synthetic substrates. For the enzymatic assays, these fluorescent substrates showed similar advantages as the radioactively labelled substrates, but not their disadvantages: thus, they can be easily used in the clinical laboratories. A new area in the field of research on lysosomal genetic diseases, is the experimental study of the metabolism in the intact living cell. The lipoproteins route is the best way to the lysosomal compartment and fluorescent lipids incorporated into lipoproteins allow to examine the lysosomal metabolism of these lipids simultaneously, by microscopic and biochemical techniques.     

Lithium monoxide anion: a ground-state triplet with the strongest base to date

Lithium monoxide anion (LiO(-)) has been generated in the gas phase and is found to be a stronger base than methyl anion (CH(3)(-)). This makes LiO(-) the strongest base currently known, and it will be a challenge to produce a singly charged or multiply charged anion that is more basic. The experimental acidity of lithium hydroxide is DeltaH degrees (acid) = 425.7 +/- 6.1 kcal.mol(-1) (1 kcal = 4.184 kJ) and, when combined with results of high-level computations, leads to our best estimate for the acidity of 426 +/- 2 kcal.mol(-1).