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Dudka J.,Independent Medical Biology Unit | Iwan M.,Independent Medical Biology Unit | Walczyna B.,District Specialist Hospital of Stefan Cardinal Wyszynski in Lublin | Wronecki L.,District Specialist Hospital of Stefan Cardinal Wyszynski in Lublin | And 3 more authors.
Annales Universitatis Mariae Curie-Sklodowska, Sectio DDD: Pharmacia

Some cancer cells are typically characterized by hypoxia which is more resistant to radiotherapy and most common anticancer drugs. These specific phenomena encouraged researchers to the investigate new hypoxic-cell-selective cytotoxins. Tirapazamine (TPZ) is a representative of the drug-candidates group which demonstrates a considerable higher cytotoxic effect against hypoxic and then normoxic tumor cells studied under the same conditions. Taking into account that solid tumor does not only consist of hypoxic but also normoxic cells, a rational therapy should combine administration of classical anticancer therapy and TPZ. Results of some studies conducted under laboratory conditions indicated some benefits of such a schedule. Because doxorubicin (DOX), a widely used chemotherapeutic drug, has a similar mechanism of action as TPZ, we tested the hypothesis assuming interaction of both compounds in rats referring to blood toxicity. In this study we evaluated peripheral blood automatic smear in rats repeatedly treated with both DOX and TPZ. The major findings are that TPZ may statistically significantly change the relative amount of lymphocytes, MPV MCV and RDW in rats treated with DOX. Collectively, these findings suggest interactions between TPZ and DOX in relation to some red cells, white cells and platelets parameters, but the clinical risk of this phenomenon seems to be acceptable during chemotherapy. However, future studies are needed to assess the importance of anisocytosis as a result DOX-TPZ interaction. Source

Korga A.,Medical University of Lublin | Dudka J.,Medical University of Lublin | Burdan F.,Medical University of Lublin | Sliwinska J.,Medical University of Lublin | And 2 more authors.
Oxidative Medicine and Cellular Longevity

Oxidative stress and disorders in calcium balance play a crucial role in the doxorubicin-induced cardiotoxicity. Moreover, many cardiotoxic targets of doxorubicin are regulated by iodothyronine hormones. The aim of the study was to evaluate effects of tetraiodothyronine (0.2, 2mg/L) on oxidative stress in the cardiac muscle as well as contractility and cardiomyocyte damage markers in rats receiving doxorubicin (1.5mg/kg) once a week for ten weeks. Doxorubicin was administered alone (DOX) or together with a lower (0.2T 4 + DOX) and higher dose of tetraiodothyronine (2T 4 + DOX). Two groups received only tetraiodothyronine (0.2T 4, 2T 4). Coadministration of tetraiodothyronine and doxorubicin increased the level of lipid peroxidation products and reduced RyR2 level when compared to untreated control and group exposed exclusively to doxorubicin. Insignificant differences in SERCA2 and occasional histological changes were observed. In conclusion, an increase of tetraiodothyronine level may be an additional risk factor of redox imbalance and RyR2 reduction in anthracycline cardiotoxicity. Copyright 2012 Agnieszka Korga et al. Source

Dudka J.,Medical University of Lublin | Korga A.,Medical University of Lublin | Gieroba R.,Medical University of Lublin | Walczyna B.,Medical University of Lublin | And 3 more authors.
Annales Universitatis Mariae Curie-Sklodowska, Sectio DDD: Pharmacia

The most evidence suggests that the major cause of doxorubicin (DOX) cardiotoxicity is reactive oxygen species and consequently oxidative stress. The accumulation of oxidative damages leading to mitochondrial dysfunction results in contractility disorders. In a cell adaptive process against oxidative stress, the transcription factor Nrf2 (Nfe2) plays a crucial role by stimulating expression of genes controlling synthesis of enzymes taking part in oxidative defence and red-ox equilibrium, e.g. glucose-6-phosphate dehydrogenase, phosphogluconate dehydrogenase and malic enzyme. Expression of genes responsible for the synthesis of these enzymes is controlled by iodothyronine hormones. These facts lead to an assumption that the impact of anthracyclines on oxidative stress may differ in hyperthyroid and euthyroid individuals. In these studies first of all we tested the hypothesis that symptoms of oxidative stress may be evident long time since last dose of DOX and if hypothyreosis may change myocardium antioxidative response in rats which received DOX. There was no statistical difference in Nfe2 expression in hearts of rats after doxorubicin administrations (group of DOX) versus controls. In this group there were no statistical differences in cardiac NADPH and total mitochondrial glutathione concentrations and GSH/GSSG ratio comparing to the controls. Moreover, any changes in all tested parameters were observed between DOX vs. DOX+4T4. We concluded that after three weeks since last doxorubicin administration there were no significant signs of oxidative stress in the heart, and that in our study conditions there was no interaction of DOX and thyroxin referring to oxidative stress in the myocardium. Copyright © 2011 Medical University in Lublin. Source

Matysiak W.,Medical University of Lublin | Dudka J.,Medical University of Lublin | Korga A.,Medical University of Lublin | Zieba J.,Medical University of Lublin | And 4 more authors.
Annales Universitatis Mariae Curie-Sklodowska, Sectio DDD: Pharmacia

Tirazapamine is a drug that has been shown to be a selective anticancer compound which was proved, in the latest studies, more efficient in concomitant treatment with other chemotherapeutic agents. In previous studies evidence suggested that the predominant mechanism DOX and TPZ cell toxicity is linked with the generation of reactive oxygen species. Moreover, under normal cell condition, CP decreased the level of reduced glutathione changing red-ox status. Then Redox equilibrium differences may have an impact on lipids, hydrocarbons and proteins metabolic transformations. In our study we tested the effect of TPZ in combination with DOX, CP and 5-FU on myocytes oxidative stress, triglycerides, glucose and proteins levels. The rats were treated (i.p.) with two doses (5 i 10 mg/kg b.w.) of tirapazamine, 2h before administration of 1.8 mg/kg b.w. of doxorubicin, 2 mg/kg b.w of cisplatin or 10 mg/kg b.w. of 5-fluorouracil. All tested drugs were administered once a week over a period of 6 weeks and a week after the last dose was given, and the obtained skeletal muscle samples were taken to be tasted. The data presented in this study support the assumption that TPZ changed the red-ox equilibrium in skeletal muscle of rats treated at the same time with DOX or FU. TPZ also caused metabolic disorders in rats treated simultaneously with CP. On the other hand, the lack of relationship between oxidative stress and metabolic disorders in the tested pairs of drugs suggested that these phenomena are independent under experimental conditions. Source

Sliwinska J.,Medical University of Lublin | Dudka J.,Medical University of Lublin | Korga A.,Medical University of Lublin | Burdan F.,Medical University of Lublin | And 4 more authors.
Oxidative Medicine and Cellular Longevity

Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug, passes the same red-ox transformation as DOX. The aim of the study was to evaluate an effect of tirapazamine on oxidative stress, contractile protein level, and cardiomyocyte necrosis in rats administered doxorubicin. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses, 5 (5TP) and 10mg/kg (10TP), while doxorubicin was administered in dose 1.8mg/kg (DOX). Subsequent two groups received both drugs simultaneously (5TP+DOX and 10TP+DOX). Tirapazamine reduced heart lipid peroxidation and normalised RyR2 protein level altered by doxorubicin. There were no significant changes in GSH/GSSG ratio, total glutathione, cTnI, AST, and SERCA2 level between DOX and TP+DOX groups. Cardiomyocyte necrosis was observed in groups 10TP and 10TP+DOX. © 2012 Justyna Sliwinska et al. Source

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