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      Effects of Pyrrolidine Dithiocarbamate on Antioxidant Enzymes in Cardiomyopathy Induced by Adriamycin in Rats

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          Abstract

          Objective: The clinical usefulness of adriamycin (ADR) is restricted by the frequent induction of dose-dependent chronic cardiomyopathy. Previous studies on ADR cardiotoxicity have reported that the formation of free reactive oxygen radicals might be involved in ADR cardiotoxicity. Pyrrolidine dithiocarbamate (PDTC) is a potent antioxidant in vivo and in vitro. The present study was undertaken to examine the effects of PDTC on antioxidant enzymes in cardiomyopathy induced by ADR in rats. Methods: Thirty-two male Wistar rats were randomly divided into 4 groups: control, ADR, PDTC, and ADR+PDTC. After 30 days, myocardial histopathological and electron microscopic examinations were performed: the myocardial content of superoxide anion and lipid peroxides were examined; the myocardial total antioxygenation capability (T-AOC) and activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were examined; myocardial GSH-Px, Mn-SOD and Cu,Zn-SOD gene expressions were examined by RT-PCR analysis, and the myocardial expression of GSH-Px, Mn-SOD and Cu,Zn-SOD proteins was assessed by Western blot analysis. Results: At 30 days, ADR-induced cardiomyopathy was confirmed by structural examination. The changes were prevented by PDTC. Myocardial superoxide anion and lipid peroxides were increased by ADR, and these changes were also inhibited by PDTC. ADR decreased myocardial T-AOC and the activity of GSH-Px and SOD, and these changes were likewise inhibited by PDTC. mRNA and protein expression of GSH-Px and Mn-SOD were depressed by ADR treatment and prevented by PDTC. Cu,Zn-SOD mRNA and protein levels were not significantly changed by ADR or PDTC. Conclusion: PDTC prevented ADR cardiomyopathy in rats by upregulating GSH-Px and SOD activation, which is associated with changes in the expression of GSH-Px and Mn-SOD transcript and protein levels.

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          Most cited references 10

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          Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells

          Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.
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            Doxorubicin-induced persistent oxidative stress to cardiac myocytes.

            We recently reported a cardioselective and cumulative oxidation of cardiac mitochondrial DNA (mtDNA) following subchronic administration of doxorubicin to rats. The mtDNA adducts persist for up to 5 weeks after cessation of doxorubicin treatment. Since the evidence suggests that this persistence of mtDNA adducts cannot be attributed to a lack of repair and replication, we investigated whether it might reflect a long-lasting stimulation of free radical-mediated adduct formation. Male Sprague-Dawley rats received weekly s.c. injections of either doxorubicin (2 mg/kg) or an equivalent volume of saline. Cardiac myocytes isolated from rats following 6 weekly injections of doxorubicin expressed a much higher rate of reactive oxygen species (ROS) formation compared to saline controls. This higher rate of ROS formation persisted for 5 weeks following the last injection. Associated with this was a persistent depression of GSH in heart tissue, while protein-thiol content was not markedly altered. These data suggest that the accumulation and persistence of oxidized mtDNA may be due, not to the stability of the adducts, but to some as yet undefined toxic lesion that causes long-lasting stimulation of ROS generation by doxorubicin. This persistent generation of ROS may contribute to the cumulative and irreversible cardiotoxicity observed clinically with the drug.
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              Early and delayed clinical cardiotoxicity of doxorubicin.

              Five hundred thirty-four evaluable patients with breast cancer were treated with a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide. The total planned dose of doxorubicin was 300 mg/m2 in patients with Stage II or III disease, and 450 mg/m2 in patients with isolated recurrences. The median time interval from start of adjuvant therapy to time of analysis was 68 months. Two percent had congestive heart failure associated with doxorubicin. Fifteen patients showed myocardial dysfunction attributed to either additional treatment with potentially cardiotoxic drugs for recurrent disease or other causes. The incidence of congestive heart failure was 1% in patients treated with up to 300 mg/m2, and 4% in patients who received 450 mg/m2 of doxorubicin. The median time interval from the end of doxorubicin to development of congestive heart failure was 1 month (range, 0-33 months). None of the 326 patients who have been followed 3 or more years (162 followed 5 or more years) since completion of doxorubicin therapy have developed congestive heart failure which was considered to be related from that therapy.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2008
                August 2008
                31 March 2008
                : 111
                : 2
                : 119-125
                Affiliations
                aDepartment of Radiotherapy, Tumor Hospital of Harbin Medical University, Harbin, bDepartment of Cardiology, Shanghai Jiaotong University Affiliated First People’s Hospital, Shanghai, and cDepartment of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, PR China
                Article
                119699 Cardiology 2008;111:119–125
                10.1159/000119699
                18376123
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 2, References: 20, Pages: 7
                Categories
                Original Research

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