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INTRODUCTION:Newly developed antineoplastic drugs have resulted in improvements in morbidity and mortality from many forms of cancers. However, some of these new chemotherapeutic agents have potentially lethal side effects, which are now being exposed with their widespread use. Gemcitabine is a nucleoside analog, which is a commonly used agent for various solid organ malignancies. Phase 1 and 2 trials with gemcitabine did not show significant risk for cardiotoxicity / however, with its widespread clinical use over the last decade, a few cases of cardiotoxicity related to gemcitabine use have been reported. Cardiomyopathy after the use of gemcitabine monotherapy is extremely rare / and only one such case has been reported in detail previously.CASE PRESENTATION:We report a case of a 56-year-old African American man with pancreatic cancer who presented with signs and symptoms of congestive heart failure after being treated with gemcitabine for two cycles (six doses). A two-dimensional echocardiography showed left ventricular ejection fraction of 15 to 20 percent with global hypokinesia. With the absence of significant risk factors for coronary artery disease and a strong temporal relationship with the initiation of chemotherapy, it was concluded that our patient's cardiomyopathy was related to the use of gemcitabine. Gemcitabine was discontinued and our patient responded well to standard heart failure therapy. Two months later, a repeat echocardiogram showed significant improvements in left ventricular systolic function.CONCLUSIONS:Gemcitabine should be considered as a potential cause of cardiomyopathy in patients receiving chemotherapy with this drug. We need further studies to look into potential mechanisms and treatments of gemcitabine-induced cardiac dysfunction.

Class of 2017 Abstract / Objectives: Specific Aim #1: Describe the incidence and degree of severity of cardiac dysfunction in case studies, retrospective chart analyses, and prospective randomized clinical trials for patients treated with pertuzumab containing regimens for neoadjuvant treatment of locally advanced, inflammatory, or early stage HER2+ BC, or for treatment of metastatic HER2+ BC. Specific Aim #2: Describe the frequency of cardiac safety monitoring for patients undergoing treatment with pertuzumab containing regimens for HER2+ BC within these case studies, retrospective chart analyses, and prospective randomized clinical trials. Methods: Case reports, retrospective chart analyses, and prospective, randomized, controlled trials were identified by search of PubMed and Embase databases, as well as through the Google Scholar search engine. The search strategy included the following keywords: epidermal growth factor receptor 2, erbB-2 genes, pertuzumab, cardiotoxicity, left ventricular function, and left ventricular dysfunction. Reviews were ineligible. All studies that examined the cardiac safety of pertuzumab containing regimens for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer were considered eligible for this systematic review, regardless of sample size. Results: So far, the search strategy retrieved 3 studies that evaluated the cardiac toxicity outcomes of pertuzumab containing regimens. All studies were conducted for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer. Conclusions: The incidence of cardiotoxicity due to treatment with pertuzumab containing regimens for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer remains relatively low. However, the potential severity of cardiac effects related to pertuzumab containing regimens is an important consideration when using these regimens in patients who have any existing risk factors for decreased cardiac function. This systematic review providers a more thorough understanding of the incidence and severity of cardiac adverse effects related to pertuzumab containing regimens since the time pertuzumab was first introduced as an option for HER2+ breast cancer patients.

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Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Introduction: Doxorubicin (DOX), infamously known as the “red devil,” is considered the most effective antineoplastic drug utilized in oncologic practice today. However, its clinical use is hampered due to cumulative, dose-dependent cardiotoxicity, which can lead to reduced quality of life, irreversible heart failure and death. The mechanisms involved in the pathogenesis of cardiotoxicity have not been fully elucidated, but have previously been demonstrated to involve oxidative stress, calcium dysregulation and mitochondrial dysfunction. Since the mitochondria play a critical role in generation of reactive oxygen species, the maintenance of calcium homeostasis and are the most extensively damaged by DOX, they have become the main focus of novel therapeutic interventions. The morphology and function of these dynamic organelles are regulated in part by mitochondrial fission and fusion events, as well as mitochondrial quality control systems. Since mitochondrial morphology is often associated with crucial cellular functions, this study aimed to investigate the long-term effects of DOX on mitochondrial dynamics and the mitochondrial quality control systems, mitophagy and the ubiquitin-proteasome pathway (UPP). Additionally, since the mitochondria and the endoplasmic reticulum (ER) are two interconnected organelles, and both play a role in maintaining calcium homeostasis, this study further assessed the effects of chronic DOX treatment on ER function and calcium status. Materials and Methods: In order to fully establish the effect of chronic DOX treatment in vitro, two cardiac cell lines were utilized in this study. H9C2 cardiomyoblasts and humanderived Girardi heart cells were cultured under standard culture conditions until ± 70-80% confluency was reached, where after treatment commenced. Cells were treated daily with 0.2 and 1.0 μM of DOX for 96 and 120 hours in order to simulate chronic, cumulative cardiotoxicity. Cell viability and apoptotic cell death were assessed with the MTT assay and Caspase Glo 3/7 assays, respectively. The expression of proteins involved in mitochondrial dynamics, mitochondrial biogenesis, the ubiquitin-proteasome pathway, mitophagy and ER stress were determined with Western blotting. Organelle morphology was visualized with fluorescence microscopy, and flow cytometry was used to assess mitochondrial and ER load. In order to determine the oxidative capacity, stress and status within the cells following treatment, the Oxygen radical absorbance capacity (ORAC), Thiobarbituric acid reactive substances (TBARS) and Glutathione (GSH) assays were employed respectively. Finally, intracellular and mitochondrial calcium was assessed and quantified with superresolution structured illumination microscopy (SR-SIM) and flow cytometry respectively. Results: DOX significantly reduced cell viability and increased apoptosis in both in vitro cardiac cell models. This study further demonstrated that the expression of mitochondrial fusion proteins, Mfn 1 and Mfn 2 were significantly downregulated, whilst the regulators of fission, Drp1 and hFis1, were significantly elevated, therefore shifting the balance of mitochondrial dynamics towards fission. Unopposed and elevated mitochondrial fission was clearly evident from the morphology of these organelles, which displayed short, highly fragmented mitochondria with a dispersed network following treatment. Chronic DOX also downregulated the regulator of mitochondrial biogenesis, PGC-1α, thus inhibiting the formation of new, functional mitochondria. The E3 ligases, MARCH5 and Parkin were highly upregulated following treatment, indicating activation of the UPP and mitophagy. Although chronic DOX stimulated K48 ubiquitination following treatment, it inhibited the catalytic activity of the 26S proteasome, therefore blocking proteasomal degradation. Although the antioxidant capacity (measured as ORAC) was significantly enhanced by both concentrations of DOX, an increase in oxidative stress status was shown following DOX treatment. In this regard lipid peroxidation significantly increased, while redox status of the endogenous antioxidant, glutathione, significantly decreased. Additionally chronic DOX treatment induced ER stress, which lead to an increase in cytosolic and mitochondrial calcium. In response to ER stress, the unfolded protein response (UPR) was then stimulated. Discussion: Results from this study indicate that chronic DOX treatment disrupts the balance of mitochondrial dynamics, favouring mitochondrial fission. Mitochondrial fragmentation is mediated by the downregulation of fusion proteins regulated by the E3 ubiquitin ligase, MARCH5 as well as by the increase in mitochondrial calcium. Mitochondrial fission results in mitophagy, an adaptive response to protect the cardiac cell against damaged mitochondria. This study also indicates that during chronic DOX-induced cardiotoxicity ER stress and the UPR are induced, which is possibly responsible for the disruption in calcium homeostasis. The inhibition of mitochondrial biogenesis coupled with elevated mitophagy as observed in this chronic study, elucidates a plausible mechanism whereby DOX induces mitochondrial dysfunction. Unregulated mitochondrial fragmentation and inhibited mitochondrial biogenesis are known to regulate various cardiomyopathies, therefore since both these effects are induced by chronic DOX treatment suggests a mechanism whereby cardiotoxicity, and ultimately heart failure are produced. This study provides new insight into the role of chronic DOX plays in altering mitochondrial dynamics and mitochondrial quality control systems. Further investigations targeted at limiting mitochondrial fission may reduce the cardiovascular side effects associated with DOX. / AFRIKAANSE OPSOMMING: Inleiding: Doksorubisien (DOX), ook bekend as die “rooiduiwel,” word beskou as die mees effektiewe anti-neoplastiese middel wat tans in onkologie praktyke gebruik word. Die kliniese gebruik hiervan word gerem deur die kumulatiewe dosis-afhanklike kardiotoksisiteit wat tot verlaagde lewenskwaliteit, onomkeerbare hartversaking, en tot die dood kan lei. Die meganismes wat by die kardiotoksiese patogenese betrokke is, is nog onbekend, maar die meganisme het moontlik te doen met oksidatiewe stres, kalsiumwanregulering en mitochondriale wanfunksionering. Omrede die mitochondria ‘n kritieke rol in die vorming van reaktiewe suurstofspesies speel, asook die handhawing van kalsiumhomeostase en die mees beskadigde organelle deur DOX, het die hooffokus na nuwe terapeutiese intervensies verskuif. Die morfologie en funskie van hierdie dinamiese organelle word gereguleer deels deur mitochondriale fragmentering en fussie, asook mitochondriale kwaliteitsbeheersisteme. Omrede mitochondriale morfologie geassosieer is met noodsaaklike sellulêre funksies, het hierdie studie gepoog om die langtermyneffkte van DOX op mitochondriale dinamika en die mitochondriale kwaliteitsbeheersisteme, mitofagie en die ubikwitien-proteosoomweg (UPW) te ondersoek. Siende dat die mitochondria en die endoplasmiese retikulum (ER) twee interverweefde organelle is, en beide ‘n rol speel in die handhawing van kalsiumhomeostase, het hierdie studie verder die effekte van chroniese DOX behandeling op ER funksie en kalsiumstatus ondersoek. Materiaal en Metodes: Om die effek van chroniese DOX behandeling in vitro te verstaan in hierdie studie, is twee hartsellyne gebruik. H9C2 kardiomioblaste en menslike Girardi hartselle is onder standaardtoestande tot ± 70-80% konfluensie bereik is gekweek, waarna behandeling begin is. Selle is daagliks met 0.2 en 1.0 μM DOX vir 96 en 120 uur behandel om chroniese en kumulatiewe kardiotoksisiteit n ate boots. Selvatbaarheid en apoptotiese seldood is onderskeidelik ondersoek deur middel van die MTT en Caspase Glo 3/7 toetse. Die proteïenuitdrukking betrokke by mitochondriale dinamika, mitochondriale biogenese, die ubikwitien-proteosoom weg, mitofagie en ER stres is deur middel van westerse afblatting bepaal. Organelmorfologie is deur middel van fluoresensie mikroskopie gevisualiseer, en vloeisitometrie was gebruik om die aantal mitochondria en ER lading te bepaal. Om die oksidatiewe kapasiteit, stres en status binne die selle na behandeling te bepaal, is die ORAC, TBARS en GSH toetse onderskeidelik gebruik. Laastens was die intrasellulêre en mitochondriale kalsium ondersoek en gekwantifiseer met superresolussie gestruktureerde illuminasie mikroskopie (SR-SIM) en vloeisitomerie. Resultate: DOX het selvatbaarheid betekenisvol verlaag en apoptose in beide in vitro kardiale selmodelle verhoog. Hierdie studie het verder aangetoon dat die uitdrukking van mitochondriale fussie proteïene, Mfn 1 en Mfn 2 betekenisvol afgereguleer is, terwyl die reguleerders van fragmentering, Drp1 en hFis1, betekenisvol verhoog is en daardeur die balans van mitochondriale dinamika na fussie verskuif. Onverhinderde en verhoogde mitochondriale fragmentering is duidelik sigbaar deur die morfologie van die organelle, wat as kort, hoogsgefragmenteerde mitochondria met ‘n verspreide netwerk na behandeling vertoon. Chroniese DOX het ook die mitochondriale biogenese reguleerder, PGC-1α, afgereguleer en daardeur die vorming van nuwe, funksionele mitochondria geinhibeer. Die E3 ligase, MARCH5 en Parkin is hoogs opgereguleer na behandeling, wat aktivering van UPW en mitofagie aantoon. Alhoewel chroniese DOX K48 ubikwitinering na behandeling gestimuleer het, het dit die katalitiese aktiwiteit van die 26S proteasoom geinhibeer en dus die proteosomale degradasie geblokkeer. Antioksidantkapasiteit en oksidatiewe status was betekenisvol na behandeling wat gevolglik tot hoë vlakke oksidatiewe skade binne die selle gelei het. Addisioneel het chroniese DOX behandeling ER stres geïnduseer wat tot ‘n toename in sitosoliese en mitochondriale kalsium gelei het. In reaksie op die ER stres is die UPW gestimuleer. Bespreking: Resultate van hierdie studie het aangetoon dat chroniese DOX behandeling die balans van mitochondriale dinamika onderbreek en sodoende mitochondriale fragmentering bevoordeel. Mitochondriale fragmentering word gemediëer deur die afregulering van fussie proteïene wat deur die E3 ubikwitienligase, MARCH5, gereguleer word, en ook deur die toename in mitochondriale kalsium. Mitochondriale fragmentering induseer mitofagie, ‘n aanpassingsreaksie om die hartselle teen beskadigde mitochondria te beskerm. Hierdie studie toon verder ook dat gedurende chroniese DOX-geïnduseerde ER stres, word die UPW ook geïnduseer, wat moontlik dan verantwoordelik is vir die ontwrigting van kalsiumhomeostase. Die inhibering van mitochondriale biogenese gekoppel met verhoogde mitofagie soos waargeneem in hierdie studie, verklaar ‘n moontlike meganisme waardeur DOX mitochondriale wanfunksionering veroorsaak. Ongereguleerde mitochondriale fragmentering en geinhibeerde mitochondriale biogenese is bekend om verskeie kardiomiopatieë te reguleer. Omrede beide hierdie effekte geinduseer word deur chroniese DOX behandeling kan dit moontlik ‘n meganisme voorstel waarby kardiotokiese en uiteindelik hartversaking ontwikkel. Hierdie studie bied nuwe insig in die rol wat chroniese DOX speel in die wysiging van mitochondriale- dinamika en kwaliteitskontrole sisteme. Verdere ondersoeke wat die mitochondriale fragmentering kan verminder mag moontlik die kardiovaskulêre newe-effekte wat met DOX behandeling geassosieer is, verlaag. / National Research Foundation (NRF)

Background: In breast cancer patients, the administration of Trastuzumab and Doxorubicin is associated with an increased risk of cardiotoxicity. The aim of the study was to determine if the antioxidant probucol would be useful in attenuating this drug induced cardiotoxicity. Methods: In an acute murine model of chemotherapy induced cardiomyopathy, wild-type C57Bl/6 mice received one of the following regimens: (1) control; (2) doxorubicin; (3) trastuzumab; (4) dox+trastuzumab; (5) probucol; (6) probucol +dox; (7) probucol+trastuzumab; (8) probucol+dox+trastuzumab. Serial murine echocardiography with tissue Doppler imaging was performed daily. Histological and biochemical studies were conducted at day 10 of the experiment. Results: Mice treated with prophylactic probucol demonstrated minimal cardiotoxicity compared with those treated with doxorubicin+trastuzumab. Survival rate was only 27% at day 3 of the experiment in the doxorubicin+trastuzumab group compared to 82% of mice receiving probucol+ doxorubicin+trastuzumab. Survival, apoptosis and histological remodeling were preserved in mice prophylactically treated with probucol following the administration of trastuzumab+doxorubicin. Conclusion: The synergistic cardiotoxicity of trastuzumab plus doxorubicin is attenuated by the antioxidant probucol.

Background: In breast cancer patients, the administration of Trastuzumab and Doxorubicin is associated with an increased risk of cardiotoxicity. The aim of the study was to determine if the antioxidant probucol would be useful in attenuating this drug induced cardiotoxicity. Methods: In an acute murine model of chemotherapy induced cardiomyopathy, wild-type C57Bl/6 mice received one of the following regimens: (1) control; (2) doxorubicin; (3) trastuzumab; (4) dox+trastuzumab; (5) probucol; (6) probucol +dox; (7) probucol+trastuzumab; (8) probucol+dox+trastuzumab. Serial murine echocardiography with tissue Doppler imaging was performed daily. Histological and biochemical studies were conducted at day 10 of the experiment. Results: Mice treated with prophylactic probucol demonstrated minimal cardiotoxicity compared with those treated with doxorubicin+trastuzumab. Survival rate was only 27% at day 3 of the experiment in the doxorubicin+trastuzumab group compared to 82% of mice receiving probucol+ doxorubicin+trastuzumab. Survival, apoptosis and histological remodeling were preserved in mice prophylactically treated with probucol following the administration of trastuzumab+doxorubicin. Conclusion: The synergistic cardiotoxicity of trastuzumab plus doxorubicin is attenuated by the antioxidant probucol.

Made available in DSpace on 2014-06-11T19:28:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-05-02Bitstream added on 2014-06-13T20:36:54Z : No. of bitstreams: 1 assumpcao_jucv_me_arafcf.pdf: 678214 bytes, checksum: 9acfe9078c5e33e1edcaa979ba032dca (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Universidade Estadual Paulista (UNESP) / Neste estudo investigou-se o perfil farmacocinético da DOX administrada na forma de microemulsão lipídica, em dose única i.v (6 mg/kg), a ratos Wistar (n=12; 250 g) e comparou-se ao perfil farmacocinético da doxorrubicina administrada na forma de cloridrato em solução aquosa. Ainda, avaliou-se a atividade da CKMb nos dois grupos de animais antes e após a administração das formulações com o objetivo de evidenciar a cardiotoxicidade do produto. Para a avaliação do perfil farmacocinético foram colhidas amostras seriadas de sangue (0 – 16 h) através de cânulas previamente implantadas na veia femoral, e para a avaliação da atividade de CKMb foram colhidas amostras de sangue nos tempos zero, 1 h e 12 h após a administração das formulações. Para a determinação da doxorrubicina em amostras de sangue e nas formulações, desenvolveu- se e validou-se um método analítico por HPLC com detecção por fluorescência (exc= 480 nm; em= 560 nm), empregando-se coluna Xterra (C18, 5 µm, 3,9 x 150 mm) e fase móvel composta por 25% de acetonitrila e 75% de água na presença de ácido fórmico (0,1%) e de solução de amônia 25% (0,1%), pH 3,0 , com fluxo de 0,8 mL/min, em modo gradiente. Para as determinações da atividade da CKMb utilizou-se o kit labtest. O método analítico desenvolvido demonstrou limites de confiança adequados para a sua aplicação na determinação da DOX em formulações e em amostras de plasma para a avaliação do seu perfil farmacocinético. Os parâmetros farmacocinéticos que apresentaram diferenças estatisticamente significativas (p<0,05, Mann-Whitney) entre a microemulsão e solução aquosa, apresentados como média (IC 95), foram respectivamente: Vd (L/kg) = 38,23 (24,94 – 51,50) vs 68,85 (55,69 – 82,00); tss (h) = 45,33 ( 39,45 – 58,20) vs 33,23 ( 27,7 – 38,75); β(h-1 )= 0,0014 (0,00072 – 0,00208) vs 0,00078... / The present study investigated the DOX pharmacokinetic profile when administered as a lipid microemulsion in a single dose (6 mg/kg, IV) to Wistar rats (n=12; 250g) and compared it to the pharmacokinetic profile of doxorubicin administered as hydrochloride in aqueous solution. With the purpose of demonstrating the cardiotoxicity of the product it also evaluated the CKMB activity in both animal groups before and after administration of the formulations. Serial blood samples were obtained (0 – 16h) through cannulas previously implanted into the femoral vein to evaluate the pharmacokinetic profile. To evaluate the CKMB activity, blood samples were collected after the formulation was administered at times zero, 1h and 12h. An analytical method by HPLC with fluorescence detection (exc= 480 nm; em= 560 nm) was developed and validated for the determination of doxorubicin in blood samples and in the formulations. The column used as stationary phase was Xterra  (C18, 5 µm, 3.9 x 150 mm) and the mobile phase was composed of 25% of acetonitrile and 75% of water in presence of formic acid (0.1%) and ammonia solution 25% (0.1%), pH 3.0 at a flow rate of 0.8 mL/min, gradient mode. The developed method demonstrated appropriate safety limits to its use in determining doxorubicin in formulations and in plasma samples, and therefore to evaluate the DOX pharmacokinetic profile. For the determination of CKMB activity it was used the Labtest. The pharmacokinetic parameters that showed statistically significant differences (p<0.05, Mann-Whitney) between the microemulsion and the aqueous solution, presented as medians (IC 95), were respectively: Vd (L/kg) = 38.23 (24.94 – 51.50) vs 68.85 (55.69 – 82.00); tss (h) = 45.33 (39.45 – 58.20) vs 33.23 ( 27.70 – 38.75); β(h-1 )= 0.0014 (0.00072 – 0.00208) vs 0.00078 ( 0.0004386 – 0.001076) and t1/2 (h) = 9.24 (5.31 – 13.17) vs 16.51 ... (Complete abstract click electronic access below)

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