CARDIOTOXICITY OF ANTHRACYCLINE ANTINEOPLASTIC DRUGS AND POSSIBILITIES OF PHARMACOLOGICAL CARDIOPROTECTION

- CARDIOTOXICITY OF ANTHRACYCLINE ANTINEOPLASTIC DRUGS AND POSSIBILITIES OF PHARMACOLOGICAL CARDIOPROTECTION Chronic anthracycline (ANT) cardiotoxicity is an important clinical problem which can have a substantial impact on morbidity and mortality of cancer survivors. Dexrazoxane (DEX) is the only agent with clearly evidenced cardioprotective effects in both experimental models and clinical trials. Despite intensive research, precise pathogenesis of chronic ANT cardiotoxicity and molecular mechanisms of cardioprotective effects of DEX remain unknown. Current clinical guidelines recommend not using DEX from the beginning of ANT therapy, but instead only from the cumulative ANT dose of 300 mg /m2. The aim of this work was to study functional, morphological and molecular changes associated with induction of chronic ANT cardiotoxicity and their further development in the post-exposure (follow up) period. Special attention was paid on the role of oxidative stress and possible response of protective antioxidant pathway regulated by Nrf2 as well as on mitochondrial impairment and response of mitochondrial biogenesis pathway. Chronic ANT cardiotoxicity was induced in rabbits by repeated intravenous injections of daunorubicin (DAU, 3 mg/kg, once weekly for 10 weeks). At the end of the treatment, the animals..

Cardiotoxicity of anthracycline antineoplastic drugs and possibilities of pharmacological cardioprotection

- CARDIOTOXICITY OF ANTHRACYCLINE ANTINEOPLASTIC DRUGS AND POSSIBILITIES OF PHARMACOLOGICAL CARDIOPROTECTION Chronic anthracycline (ANT) cardiotoxicity is an important clinical problem which can have a substantial impact on morbidity and mortality of cancer survivors. Dexrazoxane (DEX) is the only agent with clearly evidenced cardioprotective effects in both experimental models and clinical trials. Despite intensive research, precise pathogenesis of chronic ANT cardiotoxicity and molecular mechanisms of cardioprotective effects of DEX remain unknown. Current clinical guidelines recommend not using DEX from the beginning of ANT therapy, but instead only from the cumulative ANT dose of 300 mg /m2. The aim of this work was to study functional, morphological and molecular changes associated with induction of chronic ANT cardiotoxicity and their further development in the post-exposure (follow up) period. Special attention was paid on the role of oxidative stress and possible response of protective antioxidant pathway regulated by Nrf2 as well as on mitochondrial impairment and response of mitochondrial biogenesis pathway. Chronic ANT cardiotoxicity was induced in rabbits by repeated intravenous injections of daunorubicin (DAU, 3 mg/kg, once weekly for 10 weeks). At the end of the treatment, the animals..

Study of an iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) for the prevention of oxidative stress-induced cardiomyocyte injury

Katedra biochemických vědDepartment of Biochemical SciencesFaculty of Pharmacy in Hradec KrálovéFarmaceutická fakulta v Hradci Králov

CARDIOTOXICITY OF ANTHRACYCLINE ANTINEOPLASTIC DRUGS AND POSSIBILITIES OF PHARMACOLOGICAL CARDIOPROTECTION

- CARDIOTOXICITY OF ANTHRACYCLINE ANTINEOPLASTIC DRUGS AND POSSIBILITIES OF PHARMACOLOGICAL CARDIOPROTECTION Chronic anthracycline (ANT) cardiotoxicity is an important clinical problem which can have a substantial impact on morbidity and mortality of cancer survivors. Dexrazoxane (DEX) is the only agent with clearly evidenced cardioprotective effects in both experimental models and clinical trials. Despite intensive research, precise pathogenesis of chronic ANT cardiotoxicity and molecular mechanisms of cardioprotective effects of DEX remain unknown. Current clinical guidelines recommend not using DEX from the beginning of ANT therapy, but instead only from the cumulative ANT dose of 300 mg /m2. The aim of this work was to study functional, morphological and molecular changes associated with induction of chronic ANT cardiotoxicity and their further development in the post-exposure (follow up) period. Special attention was paid on the role of oxidative stress and possible response of protective antioxidant pathway regulated by Nrf2 as well as on mitochondrial impairment and response of mitochondrial biogenesis pathway. Chronic ANT cardiotoxicity was induced in rabbits by repeated intravenous injections of daunorubicin (DAU, 3 mg/kg, once weekly for 10 weeks). At the end of the treatment, the animals..

Anthropometric characteristics of the young Czech population and their relationship to the national sports potential

Anthropometric characteristics of young Czech men and women haven’t been measured since 2001, due to the cancellation of the traditional anthropological survey in 2011. The project “Physical activity in the Czech republic” thus offered an opportunity to fill this gap and add some useful information about another physical features of the Czech population that usualy aren’t addressed in anthropological studies. The investigated sample in the youngest age cohort (18-29 years) included 142 men and 137 women, and consisted of volunteers, who were measured during various public actions (primarily in Southern Moravia) during 2011-2012. Although the number of studied individuals was relatively small, their average height (181.0±6.2 cm in men and 168.8±6.7 in women) fits favourably the long-term trends of the secular height increase and confirms that Czech men and women belong to the very tallest in the world. Furthermore, the documented values of relative sitting height (52.63% in men, 53.38% in women) and relative arm span (101.46% in men, 99.23% in women) indicate that the Czech population can be viewed as short-limbed, when compared with other European nations. Considering that the average BMI of Czech national team members at Summer Olympics is consistently moderately above-average in comparison with other Europeans, it can be concluded that Czech men and women are physically well endowed mainly for strength sports of a more dynamic nature, where height is an important performance factor. These observations can have fundamental implications for the development and funding of talent programs, because they enable to target specific sports, whose requirements best correspond with the body type present in the Czech population.The research survey presented above was financed within the project “Creating a research team led by a reintegrated Czech researcher to determine the level of physical activity (inactivity) in chosen age groups of women and men in the Czech republic” (CZ. 1. 07/2. 3. 00/20. 0044)

Synthesis And Analysis Of Novel Analogues Of Dexrazoxane And Its Open-Ring Hydrolysis Product For Protection Against Anthracycline Cardiotoxicity In Vitro And In Vivo

Cardiotoxicity is a serious drawback of anthracycline anti-cancer drugs and dexrazoxane is the only cardioprotective agent with clinically established efficacy. Iron-mediated oxidative stress is traditionally believed to be the primary cause of anthracycline cardiotoxicity, and dexrazoxane-induced cardioprotection is attributed to iron chelating properties of its open ring metabolite, ADR-925, which may inhibit the oxidative injury. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2), and the role of oxidative stress in clinically relevant forms of cardiotoxicity has increasingly been questioned. In this study, novel analogues of dexrazoxane (MK-15, ES-5) and ADR-925 (KH-TA4, JR-159) were synthesized, and evaluated in vitro and in vivo. When examined in the leukemic cell line, HL-60, these novel analogues did not interfere with the anti-proliferative action of daunorubicin. In contrast to dexrazoxane, they had no anti-cancer effect on their own and the changes in the chemical structure resulted in a loss of TOP2 inhibitory activity. Although some of the novel compounds showed significant anti-oxidant and iron chelating properties in vitro, they did not protect isolated cardiomyocytes and rabbits from daunorubicin-induced cardiotoxicity and heart failure. Importantly, dexrazoxane has been found to be a relatively weak intracellular iron chelator and it failed to protect the isolated cardiomyocytes from model oxidative injury induced by hydrogen peroxide. However, in contrast to all novel analogues, dexrazoxane induced depletion of the TOP2 beta isoform. This isoform is typical for terminally differentiated cells and its genetic deletion has been reported to overcome anthracycline-induced cardiotoxicity. Hence, TOP2 beta, rather than (or along with) iron chelation, may be a promising target for effective cardioprotection induced by bisdioxopiperazine agents

Daunorubicin does not induce immunohistochemically detectable endothelial dysfunction in rabbit aorta and femoral artery

Anthracyclines are one of the most effective anticancer drugs ever developed, but their clinical use has been hampered by the risk of severe cardiotoxicity. In this study, we investigated whether rabbits exposed to a different cumulative dose of anthracycline suffer from immunohistochemically detectable vascular toxicity and endothelial dysfunction. Daunorubicin (3 mg/kg, i.e. 50 mg/m2) was administered i.v. to rabbits once weekly for 1-10 weeks to reach different cumulative doses of the drug (50-500 mg/m2), while control rabbits received saline. The rabbits were sacrificed either 24 hours or 7 days after reaching each particular cumulative dose, and aortas and right femoral arteries were collected for immunohistochemical analysis. Immunohistochemical analysis showed ICAM-1 staining in many aortas from both saline and daunorubicin-treated rabbits without any relationship to the anthracycline treatment. On the contrary, unlike in the lipopolysaccharide-treated or hypercholesterolemic rabbits, no distinct immunoreactivity for other markers of inflammation, oxidative and nitrosative stress (VCAM-1, 4-HNE, iNOS and nitrotyrosine) were detected in aortas and femoral arteries from either control or daunorubicin-treated animals. No relationship to the cumulative dose of the drug or post-expose set up of harvesting was found. In this study, we have demonstrated that daunorubicin does not induce gross histopathological changes in the studied arteries and it fails to induce immunohistochemically detectable endothelial dysfunction. Thus, we propose that endothelial cells are much less susceptible to anthracycline toxicity than cardiac myocytes. In addition, our data suggest that vascular toxicity of anthracyclines plays rather a minor role in the cardiovascular complications of anthracycline chemotherapy

Silymarin Dehydroflavonolignans Chelate Zinc and Partially Inhibit Alcohol Dehydrogenase

Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against Amanita phalloides intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may influence alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3-dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase