Tesi: "Chemotherapy"

1

McGrath, Pamela. "Chemotherapy : Treatment Experimentation or Illusion? : a Study into the Bioethics of Chemotherapy". Thesis, Queensland University of Technology, 1993.

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The use of cytotoxic drugs, Chemotherapy, is considered by many a valid modality in the treatment of cancer. The use of this modality in the 1950's and 1960's led to considerable success in the treatment of a number of incurable and quickly lethal rare cancers. This gave rise in the 1970's to a high expectation that Chemotherapy would provide a much needed breakthrough in the search for a cure for cancer. This optimism has led to a significant extension of the modality beyond the above known limits of successful use and created a climate which strongly supports this experimental application, although a small but increasing number of voices now challenge the legitimacy of this belief. This research explores a number of ethical issues which now arise from the continued use of this treatment modality. The discussion will center on three issues. These will be, firstly, the integrity of the treatment modality, secondly, the concerns about the experience of Chemotherapy on the individual and their family, and thirdly, the concerns involved in the public presentation of Chemotherapy and the lack of public debate. As a basis for understanding the ethical concepts used in this study into the Bioethics of Chemotherapy, a broad background of information on the relevant aspects of Normative Ethics is provided, at the beginning of this discussion. A study of the newspaper reporting of Chemotherapy is included to extend the discussion of the third issue, that of the public presentation of Chemotherapy.In conclusion, an open ended, four step plan for action is recommended.

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2

Mulholland, K. C. "Experimental chemotherapy-induced mucositis". Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.479433.

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3

Bates, Robert W. "Prodrugs for cancer chemotherapy". Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333294.

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4

Morris, D. L. "Chemotherapy of hydatid disease". Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374320.

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5

Taylor, Duncan Hugh. "Chemotherapy of Echinococcus species". Thesis, University of Nottingham, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252947.

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6

Lindner, Oana. "Chemotherapy-induced cognitive changes". Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/chemotherapyinduced-cognitive-changes(48ea95ea-4510-41b6-850e-72e733747c7c).html.

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The present thesis, entitled Chemotherapy-induced cognitive changes, is being submitted in the alternative format, by Oana Calina Lindner to The University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences, School of Psychological Sciences. The thesis consists of five empirical studies, written in article formats and three connecting chapters. The General introduction in Chapter 1, places the thesis in the context of late effects research in cancer survivors. I describe the prevalence of physical and emotional late effects, before going into more details on cognitive late effects. Chapter 2 provides a meta-analytical summary of cognitive impairments following chemotherapy in adult patients. It has already been published in Neuropsychology in 2014. Chapter 3 describes the general objectives and hypotheses of the empirical studies, and Chapter 4 provides more details on the General methods utilized in all the studies. The studies focus on pre- and post-treatment young adult cancer patients who were compared to age-, sex-, and education-matched controls. The instruments include a comprehensive neuropsychological battery, a newly designed memory task, and a complex battery of self-assessment questionnaires. Chapter 5 is the first empirical study, which will be submitted to Journal of Clinical Oncology. It describes the pattern of neuropsychological status of young adult cancer patients following treatment for lymphoma, sarcoma, breast cancer, and germ cell tumour. The impairments were specific to executive functioning, verbal memory, and visuospatial abilities. Uniquely, the chapter depicts differences between cancer groups. Because chemotherapy may not be the primary factor triggering such effects, Chapter 6 details the neuropsychological profile of a group of young adult pre-treatment patients diagnosed with the same malignancies. This chapter will be submitted to Journal of Neuropsychology. Impairments were observed on tests of attention, executive functioning and visuospatial abilities. Both Chapters 5 and 6 emphasize the importance of matching on full scale IQ in cross-sectional studies and they provide evidence that patients' performance on tests of verbal memory and executive functioning may vary as a function of age. Chapter 7 will be submitted to Psycho-Oncology and it suggests the presence of acute memory deficits after the first treatment. Finally, Chapter 8, which will be submitted to Psychosomatic Medicine, provides an in-depth description of the psycho-emotional status of cancer survivors. It describes higher levels of anxiety, depression, fatigue, and cognitive complaints, which mediated the relationship between illness perceptions and quality of life. The complex interaction between these psycho-emotional factors is interpreted within the framework of cognitive-behavioural therapies, which may provide a method to decrease the emotional burden of survivorship in clinical practice. Finally, Chapter 9 summarizes all the empirical findings whilst connecting them to previous literature and specifying future research direction.

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7

Tintoré, Gazulla Maria. "hAGT inhibitors as chemotherapy enhancers". Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/299794.

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The O6-alkylguanine DNA alkyltransferase (hAGT or MGMT) is a DNA repair protein in charge of removing alkyl adducts from the O6 position of guanines, blocking their cytotoxic effects and playing an important role as a resistance mechanism to chemotherapy in cancer patients. For these reasons, it is considered relevant as a prognosis marker of cancer and represents a potential therapeutic target. Intense research efforts have been devoted to the identification of small molecules capable of inhibiting hAGT activity and enhancing the cytotoxic effect of the alkylating agents in tumour cells. In this doctoral thesis, we have explored 10 compounds with potential inhibitory activity against hAGT. The analysis by mass spectrometry (ESI-MS) confirmed the complex formation of hAGT with 5 of them (compounds 5, 6, 7, 8 and 9). MTT cytotoxicity studies in cell culture showed that 2 compounds (5 and 8) were non-toxic and showed enhancement of carmustine toxicity. This compounds were further analysed by colony formation assays, which confirmed that compound 8 was non-toxic at long-term experiments and exhibited a stimulation effect of carmustine. Compound 8 seem to be the best candidates for hAGT inhibition, as it forms a complex with hAGT and it enhances BCNU without being toxic in MTT and colony formation assays. Due to the lack of a consistent in vitro assay for the activity of hAGT, we have devoted part of this doctoral thesis to the search of bio and nanotechnologies to detect hAGT activity which enable the evaluation of potential inhibitors of the protein. Chapter 2 describes the development of a new fluorescence method using the conformational change of a DNA Gquadruplex, the thrombin binding aptamer (TBA), as a molecular beacon for the detection of hAGT activity and the development of new inhibitor compounds. The conformational change of TBA is further explored to develop a detection platform on DNA origami which allows de quantification of the repair activity of hAGT on a single molecules basis, through the direct visualization by AFM of the interaction of TBA-thrombin when its G-quadruplex structure is restored. In addition, this work reports the synthesis of guanine derivatives modified at position 6 and properly functionalized for their incorporation into double stranded oligonucleotides that are used for the development of another novel fluorescence methodology to evaluate hAGT activity and to assess potential inhibitors as enhancers of chemotherapy. Finally, during a short stay in the University of Milan, we have developed a new sensor to detect a methylation in TBA using three types of nanoparticles: AuNPs, SPIONs and AuSPIONs. AuSPIONs combine the features of the gold coating and the magnetic core, and exhibit similar performance as AuNPs and SPIONs in UV, DLS and MRI assays to detect thrombin and a single methylation in TBA. Ths results provide the basis for the development of a new straightforward method to study hAGT activity and to evaluate potential inhibitors.
La proteïna de reparació de l’ADN alquilguanina-ADN-O6-alquiltransferasa (hAGT) elimina productes d'alquilació en la posició O6 de les guanines, bloquejant la citotoxicitat dels agents alquilants i produint resistència a la quimioteràpia. Es considera rellevant com a marcador de pronòstic en càncer i representa una potencial diana terapèutica. L’objectiu a llarg termini d’aquesta tesi doctoral és trobar inhibidors de l’activitat d’hAGT per millorar l'efecte de la quimioteràpia en pacients amb càncer. En primer lloc, es va avaluar la capacitat de 10 compostos, potencials inhibidors d’h!GT, de formar un complexe amb hAGT utilitzant espectrometria de masses, i es va estudiar la seva toxicitat en cultius cel·lulars a través d'assajos de MTT i de formació de colònies. A continuació, es desenvolupen diferents mètodes per a la detecció de l’activitat d’hAGT, per a avaluar els potencials inhibidors d’aquesta proteïna in vitro. Dos d’aquests mètodes utilitzen el canvi conformacional que es produeix en l’aptàmer d’unió a la trombina (TBA) en introduir una O6-metilguanina, substracte d’hAGT, en una de les seves tètrades centrals. En el primer mètode es va emprar el TBA per generar un sensor de fluorescència incorporant un fluoròfor i un inhibidor de fluorescència a cadascun dels seus extrems. Aquest sensor permet la detecció de la disminució en la fluorescència deguda al canvi conformacional del TBA produït per l’activitat d’hAGT. Posteriorment, el canvi conformacional del TBA va permetre dissenyar un biosensor de l'activitat d'hAGT a nivell unimolecular sobre la superficie d’un origami d'ADN. La interacció del TBA amb la seva proteïna diana, l’alfa-trombina, es va seguir per AFM per detectar que l’estructura de G-quàdruplex metilada es restableix per la reparació d’hAGT. El tercer mètode es basa en la transferència de fluorescència al centre actiu d’h!GT degut a la reparació d’un oligonucleòtid que conté una guanina modificada amb un grup alquil marcat amb un fluoròfor. Amb aquest objectiu, es va portar a terme la síntesi química d’aquesta guanina modificada. En el marc d’una estada en la Universitat de Milà, es descriu l’estudi de nanopartícules funcionalitzades amb TBAs per a detectar una metilació en una guanina utilitzant espectroscòpia d’UV, DLS o MRI, amb l’objectiu de desenvolupar un nou assaig de l’activitat reparadora d’ADN d’h!GT.

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8

Prytz, Anna, e Linda Harnfeldt. "Chemotherapy and Cancer - childrens experiences". Thesis, Kristianstad University College, Department of Health Sciences, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:hkr:diva-3754.

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With good knowledge about the disease and the treatment, the fear and worry of children and parents can be reduced. Children may be helped by painting to express their experiences. In order to have a good care, the care-personnel need to see and understand what the children need. It is important to live an as regular life as possible during the disease and its treatment. The aim of this study was to elucidate how children experience chemotherapy in conection with their cancer disease. The method that was chosen was an systematic literature review. The result was based on five qualitative articles, which could be divided into four categories: to feel afraid and worried, to feel limited, to feel different and to feel sick. Discussion: There is risk that important information that the children want to tell will go lost when parents and care-personnels communicate children’s experiences to a third part. There is reaserch telling that children may need an adult to help express their experiences.

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9

Fallon, Padraic G. "Experimental chemotherapy of Schistosoma mansoni". Thesis, Bangor University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240017.

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10

Sujendran, Vijay. "Neoadjuvant chemotherapy in oesophageal cancer". Thesis, University of East Anglia, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501118.

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Neoadjuvant chemotherapy in oesophageal cancer has gained rapid favour in le United Kingdom over the past few years. It remains controversial outside the UK, with mixed results from clinical trials. The work in this thesis begins with a review of the literature on neoadjuvant chemotherapy, and of the antimetabolites and platinum agents used. The quantitative reverse transcriptase polymerase chain reaction (qRTPCR) used to identify molecular determinants of chemosensitivity is discussed followed by a look at the clinical experience of neoadjuvant chemotherapy at a single centre. Over the past six years 194 patients in Oxford have undergone neoadjuvant chemotherapy with cisplatin and 5-flurouracil. Six patients developed progressive disease, 12 patients stopped chemotherapy early, one patient died during chemotherapy and one patient had perforation of the oesophagus. Overall chemotherapy was well tolerated among patients with no significant increase in respiratory complications and anastomotic leak following the use of neoadjuvant chemotherapy. Following the advent of neoadjuvant chemotherapy, there has been a significant decrease in circumferential resection margin involvement, compared to historical controls. Locoregional recurrence and overall survival have also improved. Cox's multivariate analysis shows circumferential resection margin to be an independent prognostic factor for locoregional recurrence and overall survival.

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11

Schirm, Sibylle, Christoph Engel, Markus Löffler e Markus Scholz. "Modelling chemotherapy effects on granulopoiesis". Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-159100.

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Background: Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far. In the present paper, we propose a comprehensive model of chemotherapy toxicity and combine it with our cell kinetic model of granulopoiesis. Major assumptions are: proportionality of cell numbers and cell loss, delayed action of chemotherapy, drug, drugdose and cell stage specific toxicities, no interaction of drugs and higher toxicity of drugs at the first time of application. Correspondingly, chemotherapies can be characterized by a set of toxicity parameters which can be estimated by fitting the predictions of our model to clinical time series data of patients under therapy. Data were either extracted from the literature or were received from cooperating clinical study groups. Results: Model assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters. Conclusion: We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment.

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12

Owolabi, Olusegun Amoo. "Studies on chemotherapy of trypanosomes". Thesis, University of Salford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293826.

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13

Miles, Philip James. "Metal complexes for cancer chemotherapy". Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627992.

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14

Schirm, Sibylle, Christoph Engel, Markus Löffler e Markus Scholz. "Modelling chemotherapy effects on granulopoiesis". BioMed Central, 2014. https://ul.qucosa.de/id/qucosa%3A12034.

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Background: Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far. In the present paper, we propose a comprehensive model of chemotherapy toxicity and combine it with our cell kinetic model of granulopoiesis. Major assumptions are: proportionality of cell numbers and cell loss, delayed action of chemotherapy, drug, drugdose and cell stage specific toxicities, no interaction of drugs and higher toxicity of drugs at the first time of application. Correspondingly, chemotherapies can be characterized by a set of toxicity parameters which can be estimated by fitting the predictions of our model to clinical time series data of patients under therapy. Data were either extracted from the literature or were received from cooperating clinical study groups. Results: Model assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters. Conclusion: We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment.

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15

Vincent, Jacob Adam. "Sensorimotor Deficits Following Oxaliplatin Chemotherapy". Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright1496136263522854.

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16

Taylor, W. B. "Control of emesis in cancer chemotherapy". Thesis, University of Newcastle upon Tyne, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378877.

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17

Nani, Frank Kofi. "Mathematical models of chemotherapy and immunotherapy". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape15/PQDD_0012/NQ34816.pdf.

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18

Petchey, M. "Lens carbohydrate metabolism and cataract chemotherapy". Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371562.

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19

Mellor, C. M. "Immunomodulation and chemotherapy of parasitic infections". Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378990.

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20

Luo, Tian. "PEGylation of paclitaxel for inhaled chemotherapy". Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/35723/.

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Pulmonary delivery offers an attractive route for delivering chemotherapeutics, with the benefits of high drug concentrations locally and low side effects systemically. However, fast clearance of small molecules in the lungs and the pulmonary toxicity are the main obstacles in this field. In this thesis, we explored the utility of polyethylene glycol-paclitaxel (PEG-PTX) conjugates to achieve sustained drug release in the lungs. Paclitaxel was linked to 6 kDa and 20 kDa PEG and the conjugates showed good stability and cytotoxicity in vitro. PEG-PTX largely increased the maximum tolerated dose of paclitaxel in mice and significantly enhanced its anti-tumor efficacy following intratracheal instillation in a lung carcinoma mouse model. PEG-PTX 20 kDa presented a prolonged residency and a sustained paclitaxel release in the lungs. This study demonstrated that PEGylation offers a potential delivery system for inhaled chemotherapy with improved anti-tumor efficacy and reduced local toxicity.

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21

Sutterfield, Shelbi Lorrae. "Microvascular function in patients undergoing chemotherapy". Thesis, Kansas State University, 2017. http://hdl.handle.net/2097/38216.

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Master of Science
Department of Kinesiology
Carl Ade
Adjuvant systemic chemotherapy for the treatment of certain cancers, particularly breast and lymphoma, adversely impacts cardiovascular health. However, the extent to which it impairs endothelial function is not well understood. Therefore, the purpose of this study was to determine if microvascular and macrovascular endothelial-dependent vasoreactivity is attenuated in breast cancer and lymphoma patients currently being treated with chemotherapy compared to healthy counterparts. With laser Doppler imaging, cutaneous microvascular function was evaluated via changes in cutaneous vascular conductance (CVC) in response to iontophoresis of acetylcholine (ACh). Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the brachial artery via ultrasonography. CVC responses to iontophoresis of ACh in the cutaneous microcirculation was significantly lower in cancer patients than in control subjects (cancer (n=7): 959.9 ± 187.3%; control (n=7): 1556.8 ± 222.2%; P = 0.03). Furthermore, FMD was significantly lower in cancer patients than in control subjects (cancer: 2.2 ± 0.6%; control: 6.6 ± 1.4%; P = 0.006). These data provide evidence of microvascular and macrovascular dysfunction in breast cancer and lymphoma patients currently undergoing adjuvant chemotherapy, which may contribute to the increased long-term risk of cardiovascular disease morbidity and mortality in those treated for cancer.

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22

Athawale, Samita. "Chemotherapy Appointment Scheduling and Operations Planning". University of Akron / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=akron1428951061.

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23

Barnes, Andrew C. "Control of furunculosis by antimicrobial chemotherapy". Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/19915.

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In vitro ativities of six fluoroquinolone antimicrobials, flumequine, sarafloxacin, PD127,391, PD117,596, enrofloxacin and Ro 09-1690, against Aeromonas salmonicida, isolated from outbreaks of furunculosis in farmed and wild Atlantic salmon (salmo salar), were evaluated in terms of minimum inhibitory concentration (MIC), bactericidal activity and the frequency at which mutation to resistance developed to the drugs compared to oxolinic acid, the 4-quinolone antibiotic currently licensed for furunculosis therapy in the UK. MICs were also determined for oxytetracycline and the β-lactam amoxycillin. In terms of MIC, the fluoroquinolones were more active than oxolinic acid with MICs reduced from 2- to 500-fold. Furthermore, the fluoroquinolones were bactericidal against both oxolinic acid-resistant and -susceptible isolates of A.salmonicida whereas oxolinic acid was not bactericidal against any bacteria tested. In addition to the increased antimicrobial activity, the frequency at which A.salmonicida mutated to resistance to the fluoroquinolones was lower than the frequency for resistance to oxolinic acid. Amoxycillin was active against all the A.salmonicida subsp. salmonicida isolates tested; however, the atypical A.salmonicida subsp. achromogenes isolates were resistant to amoxycillin with MICs in excess of 500mg/l. Ion effects were noted for the quinolones and oxytetracycline. For instance, the presence of 50mM MgCl_2 resulted in a 20- to 60- fold increase in the MICs of these drugs against the test strains. No ion effect was identified for amoxycillin. The quinolones were not affected by inoculum size but their efficacy, in terms of MIC, was reduced at the lower temperature of 10°C compared to 22°C. Mechanisms of resistance to the fluoroquinolones, oxytetracycline and amoxycillin were investigated. Low levels of resistance to the quinolones and oxytetracycline could be induced with either oxolinic acid or oxytetracycline, with each drug inducing cross resistance to the other. This phenomenon was discovered to result from alterations in outer membrane proteins, specifically the increase in expression of a 42kDa and a decrease in expression of a 37kDa protein.

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24

Wong, Ka Yeung Mark. "Drug clearance mechanisms and chemotherapy response". Thesis, The University of Sydney, 2007. https://hdl.handle.net/2123/28094.

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Cytotoxic chemotherapeutic agents have a major role in the treatment of cancers. However, many cytotoxic agents have a narrow therapeutic window with best treatment response achieved only within a small range of drug concentrations.

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25

Clark, Calum. "Scheduling chemotherapy appointments : a heuristic approach". Thesis, University of Leeds, 2010. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538443.

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26

Bossaer, John B. "Thyroid Dysfunction with Targeted Chemotherapy Agents". Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etsu-works/2361.

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1. Evaluate the mechanisms by which hyperglycemia and hypothyroidism occur in patients on certain targeted chemotherapy agents.2. Develop treatment recommendations for patients who develop these endocrine toxicities while on therapy.3. Establish appropriate monitoring guidelines for patient receiving certain targeted chemotherapy agents.

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27

AlEjielat, Rowan Fahad Ibrahim. "Pharmacogenomics of chemotherapy induced cognitive dysfunction". Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/1528.

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Cognitive decline is increasingly recognized as a side effect of chemotherapy. However, cognitive decline doesn't occur in all patients receiving chemotherapy, and there is variability in the cognitive domains affected (Ahles; JCO,Oct 20, 2012:3675-3686). Safety pharmacogenomics, i.e. using genetic variations to predict response/toxicity, offers an exciting approach to identify the subset of patients most likely to suffer from cognitive decline post chemotherapy. Consequently specific therapeutic interventions can be developed to target this group of patients, and/or alternate chemotherapeutic regimens can be used to limit toxicity, thereby offering a way to individualize therapy while minimizing toxicity. In our research we studied the effect of 16 SNPs in 6 genes on cognition in a sample of healthy older adults. We found that SNPs that affect serotonin, dopamine and glutamate levels in the brain influence cognition in a healthy sample of older adults, possibly in a domain specific manner. This allowed us to identify a group of healthy adults who inherently have lower cognitive functioning in some domains but that is still within the normal range. In addition individuals with SNPs that previously were associated with lower levels of myeloperoxidase performed better on the executive functions, verbal memory, verbal IQ and IQ. SNPs associated with lower levels were also associated with improvement in self reported verbal and visual memory post chemotherapy. APOE E2 allele was associated with higher cognitive performance compared to other alleles. However we didn't see an effect of APOE post chemotherapy. In chapter five, the effects of 31 SNPs in 15 genes on cognition post chemotherapy were evaluated in community dwelling lymphoma patients. Changes in the domains of verbal memory, visual perceptual memory, and attention of the Multiple Ability Self Report Questionnaire were observed following chemotherapy, but only when groups were stratified by genotype. Contrary to what we might expect, patients showed improvements in function after chemotherapy. However, using patient stratification based on genotype, specific groups of patients had a measurable decline in cognitive function post chemotherapy. Interestingly a SNP in the DNA replication enzyme and the target of doxorubicin topoisomerase II was associated with varying degree of self reported attention; specifically the AA genotype of rs471692 was associated with statistically significant decline in attention post chemotherapy. This indicates that cognitive changes following chemotherapy can be subtle, and stratification by genotype helps us in identifying susceptible individuals and provides some insights on the inconsistencies that are frequently reported in the literature. These results allow for identifying genetic risk factors associated with chemotherapy-induced cognitive changes, which will ultimately help in developing therapeutic approaches for the management of those deficits. Strategies to avoid chemotherapy-induced cognitive changes will be prospectively evaluated in future studies and include alternative chemotherapy and less toxic regimens, intervention strategies to improve cognitive abilities, and drug therapy to improve cognition in patients who develop chemotherapy-induced cognitive changes. The overarching goals of our studies are to help improve cancer patients' quality of life while maintaining or improving cancer cure rates.

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Alkhlaif, Yasmin. "IMPACT OF CHEMOTHERAPY ON NICOTINE DEPENDENCE". VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5175.

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Although cigarette smoke has been implicated in a causal relationship with various types of cancers, around 62% of all cancer patients are current smokers, recent quitters, or former smokers. While most patients who are smokers are motivated to quit after cancer diagnosis, 25 -30% of these patients continue to smoke. Furthermore, most quitters relapse after 2-3 years of post-chemotherapy. This represents a major health concern since several clinical studies revealed that perpetuation of smoking in cancer populations attenuates patient's well-being and quality of life. Smoking may impair healing, attenuate the efficacy of chemotherapy, increase the disease complications and diminish survival rates. However, the factors that involved in nicotine dependence in cancer patients are poorly understood. xii According to human research, it was suggested that tumor site, impact of cancer therapy and disease prognosis could be responsible of continuation of tobacco smoking among cancer patients and survivors. Recently, chemotherapy was shown to cause emotional deficits in humans (anxiety, insomnia and depression) and animals. In this project, we focused on the chemotherapeutic agent, paclitaxel, because it is widely used to treat solid tumors such as lung, head, neck and breast cancer. We previously reported that paclitaxel induced general affective deficits in mice such as anhedonia, anxiety and depression-like behaviors. We therefore hypothesized that the chemotherapeutic agent, paclitaxel may alter the rewarding and withdrawal properties of nicotine. We investigated the impact of paclitaxel on spontaneous nicotine withdrawal and nicotine reward in C57BL/6J mice by using variety of behavioral tests. Our findings showed that paclitaxel worsened the somatic and affective signs of nicotine withdrawal in male mice as well as attenuated of nicotine reward in the CPP assay. These behavioral changes were not due to an impact of nicotine metabolism by paclitaxel. Overall, paclitaxel changed the behaviors during nicotine withdrawal and reward and that suggested changing in the smoking behavior after exposure to chemotherapy.

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Pink, Daniel, Stephan Richter, Sebastian Gerdes, Dimosthenis Andreou, Per-Ulf Tunn, Christoph Busemann, Gerhard Ehninger, Peter Reichardt e Markus K. Schuler. "Gemcitabine and Docetaxel for Epithelioid Sarcoma: Results from a Retrospective, Multi-Institutional Analysis". Karger, 2014. https://tud.qucosa.de/id/qucosa%3A70562.

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Objective: Epithelioid sarcoma (ES) presents unique clinical features in comparison to other sarcoma subtypes. Data regarding the benefits of chemotherapy are very limited. Combination regimens using gemcitabine and docetaxel (Gem/Doce) have proven to be effective, especially in uterine and nonuterine leiomyosarcoma. Yet, there is no available data on the efficacy of Gem/Doce in ES. Methods: A retrospective analysis of the three participating institutions was performed. Twenty-eight patients with an ES diagnosis presented at one of the participating institutions between 1989 and 2012. Of this group, 17 patients received chemotherapy. Results: Patients’ median overall survival (OS) after the beginning of palliative chemotherapy was 21 months, and the 1-year OS was 87%. Twelve patients received Gem/Doce with a clinical benefit rate of 83%. The median progression-free survival (PFS) was 8 months for all patients receiving Gem/Doce. The best response was complete remission in 1 patient and partial remission in 6 patients. All 6 patients receiving Gem/Doce as a first-line treatment showed measurable responses with a median PFS of 9 months. Conclusions: In this retrospective study, Gem/Doce was an effective chemotherapeutic regimen for ES. Prospective studies are needed to better assess the effects of this combination drug therapy.

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Scherling, Carole Susan. "What Happens Before Chemotherapy?! Neuro-anatomical and -functional MRI Investigations of the Pre-chemotherapy Breast Cancer Brain". Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20398.

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The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

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Redzepovic, Jasmina [Verfasser]. "Meta-analysis in context : Chemotherapy versus chemotherapy combined with bisphosphonate therapy in multiple myeloma patients / Jasmina Redzepovic". Berlin : Freie Universität Berlin, 2009. http://d-nb.info/1023664585/34.

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32

MACAIONE, Ina. "Intraperitoneal chemotherapy versus adjuvant chemotherapy for treatment of colo-rectal cancer at high-risk for peritoneal carcinosis". Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/506907.

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Irving, Glen Robert Bell. "A novel approach to enhancing the effectiveness of chemotherapy : combining curcumin with FOLFOX chemotherapy for metastatic colorectal cancer". Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/35981.

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FOLFOX (5FU/leucovorin/oxaliplatin) is standard first-line therapy for metastatic colorectal cancer (mCRC), with response rates of 50%. Factors limiting the use of oxaliplatin include chemo-resistance and severe dose-related peripheral neuropathy. New interventional strategies are required which can improve disease outcomes by increasing drug efficacy whilst avoiding toxicity. Curcumin is a constituent of turmeric. Mechanisms of chemopreventive action, extensively investigated in vitro and in vivo, provide compelling evidence that curcumin exhibits efficacy in preventing neoplastic conditions and can act synergistically with chemotherapy. Laboratory endpoints must be tested clinically. In preparation for a clinical trial combining curcumin with FOLFOX, 3 lines of investigation have been followed. In vitro analysis of CRC cell lines treated with the investigative agents has explored mechanisms of chemo-resistance and the efficacy of curcumin therein. The acceptability of oral curcumin to patients has been assessed, supported by sensitive Ultra Performance Liquid Chromatography (UPLC) evaluation of curcumin and its metabolites in biomatrices. Parallel methods of biomarker profiling of plasma and urine from patients with CRC by NMR, LC-MS/MS and HD-MS have been tested for their suitability as adjuncts to trials studying mCRC. The resultant clinical method, guided by these components, devised for the assessment of curcumin and FOLFOX has been presented alongside early trial data. In vitro, curcumin was observed to overcome oxaliplatin-resistance and increase efficacy. Mechanisms of action have been proposed and sub-populations of stem-like cells suggested as potential treatment targets. Safety and tolerability of a suitable curcumin regimen have been shown clinically. Sensitive analysis of plasma, urine and tissue curcuminoids has been achieved, and prolonged mucosal exposure revealed. The proteomic and metabonomic profiles of patients with CRC are distinct from controls and could feasibly be employed as surrogate endpoints to trials. A dose-escalation study has endorsed an acceptable regimen for an on-going randomised trial investigating curcumin with FOLFOX (“CUFOX”).

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Clutter, Suzanne Davis. "Chemotherapy disrupts bone marrow stromal cell function". Morgantown, W. Va. : [West Virginia University Libraries], 2006. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=4528.

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Thesis (Ph. D.)--West Virginia University, 2006.
Title from document title page. Document formatted into pages; contains x, 180 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

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Palle, Josefine. "Optimizing Chemotherapy in Childhood Acute Myeloid Leukemia". Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9189.

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Despite major advances in our understanding of the biology of childhood acute myeloid leukemia (AML) and the development of new cytotoxic drugs, the prognosis of long-term survival is still only 60-65 %.

In the present research, we studied the pharmacokinetics of drugs used in the induction therapy of childhood AML and performed in vitro drug sensitivity testing of leukemic cells from children with AML.

The aims of the studies were to correlate the results of the analysis to biological and clinical parameters and to identify subgroups of AML with specific drug sensitivity profiles in order to better understand why treatment fails in some patients and how therapy may be improved.

Blood samples were analysed to study the pharmacokinetics of doxorubicin (n=41), etoposide (n=45) and 6-thioguanine (n=50). Doxorubicin plasma concentration and total body clearance were correlated to the effect of induction therapy, and doxorubicin plasma concentration was an independent factor for complete remission, both in univariate and multivariate analysis including sex, age, and white blood cell count at diagnosis. For etoposide and 6-thioguanine no correlation was found between pharmacokinetics and clinical effect. Children with Down syndrome (DS) tended to reach higher blood concentrations of etoposide and thioguanine nucleotides, indicating that dose reduction may be reasonable to reach the same drug exposure as in children without DS.

Leukemic cells from 201 children with newly diagnosed AML, 15 of whom had DS, were successfully analysed for in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA). We found that samples from children with DS were highly sensitive to most drugs used in AML treatment. In non-DS children, the t(9;11) samples were significantly more sensitive to cytarabine (p=0.03) and doxorubicin (p=0.035) than other samples. The findings might explain the very favorable outcome reported in children with DS and t(9;11)-positive AML. A specific drug resistance profile was found for several other genetic subgroups as well. A detailed study of MLL-rearranged leukemia showed that cellular drug sensitivity is correlated both to partner genes and cell lineage, findings that support the strategy of contemporary protocols to include high-dose cytarabine in the treatment of patients with MLL-rearrangement, both in AML and acute lymphoblastic leukemia (ALL).

Our results indicate that drug resistance and pharmacokinetic studies may yield important information regarding drug response in different sub-groups of childhood AML, helping us to optimize future chemotherapy in childhood AML.

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Smit, Egbert Frederik. "Aspects of palliative chemotherapy for lung cancer". [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 1990. http://irs.ub.rug.nl/ppn/292220588.

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Masquelier, Michèle. "Leukemia chemotherapy : experimental studies on pharmacological optimisation /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-046-X/.

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Ruth, Serge van. "Hyperthermic intracavitary chemotherapy in abdomen and chest". [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/69072.

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Witkamp, Arjen Joost. "Hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancy". [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/69091.

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Meerten, Esther van. "Chemotherapy and Chemoradiotherapy Studies in Oesophageal Cancer". [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/13209.

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41

Davies, Geraint Rhys. "Pharmacokinetics and pharmacodynamics of anti-tuberculosis chemotherapy". Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502576.

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For the first time in thirty years the tuberculosis drug development pipeline may be on the verge of delivering ultra-short course chemotherapy but continued reliance on relapse rates in clinical trials and limited understanding ofthe phenomenon ofpersistence ofM tuberculosis during treatment have made the critical pathway of early clinical development uncertain. It is demonstrated here that serial sputum colony counting,prolonged throughout the first two months oftreatment and analysed using hierarchical non-linear regression techniques has the power to detect treatment differences between combination drug regimens at very modest sample sizes.

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Kaestner, Sabine Anna. "Studies on dose-banding of cancer chemotherapy". Thesis, University of Bath, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438893.

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Richardson, Alison. "Patterns of fatigue in patients receiving chemotherapy". Thesis, King's College London (University of London), 1995. https://kclpure.kcl.ac.uk/portal/en/theses/patterns-of-fatigue-in-patients-receiving-chemotherapy(077d4a6d-4c32-4639-93aa-f442e4d1775f).html.

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44

Thomas, M. "STAT1 : a modulator of chemotherapy induced apoptosis". Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426906.

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45

Al-Samarai, Abdul-Ghani M. Ali Hasani. "Chemotherapy of parasitic infection by Herpesvirus hominis". Thesis, University of Sheffield, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318149.

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46

Shah, Iftikhar Ali. "Chemotherapy with activated charcoal adsorbed mitocycin-C". Thesis, University of Liverpool, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275012.

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47

Vacchelli, Erika. "Immunogenetic determinants of chemotherapy response in cancer". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T041.

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L’efficacité de la chimiothérapie contre la croissance tumourale repose sur l'induction d'une mort des cellules tumourales dite immunogène. Les cellules tumourales mourantes agissent alors comme un vaccin thérapeutique en stimulant une réponse immunitaire anti-tumourale capable de contrôler, voire d'éliminer, les cellules cancéreuses résiduel. Les trois marqueurs principales de la mort cellulaire immunogène (MCI), sont (i) l'exposition pré-apoptotique de la calréticuline (CRT) à la surface des cellules, (ii) la sécrétion de l'ATP pendant l'apoptose qui dépend du processus d'autophagie, et (iii) le relargage post-apoptotique de la protéine non-histone de fixation à la chromatine HMGB1 (High Mobility Group B1). CRT, ATP et HMGB1 se lient respectivement à CD91, au récepteur purinergique P2RX7 (Purinergic Receptor P2X, ligand-gated ion channel 7) et au récepteur TLR4 (Toll-like Receptor 4) situés à la surface des cellules dendritiques. En retour, ces interactions initient respectivement la phagocytose des cellules mourantes, la production de l'interleukine-1β et la cross-présentation des antigènes tumouraux aux lymphocytes T.Notre laboratoire a précédemment démontré que la chimiothérapie adjuvante présente une efficacité réduite chez des patients atteints de cancers colorectaux et du sein portant un polymorphisme d'un seul nucléotide ou SNP (Single-Nucleotide Polymorphism) compromettent la fonction des gènes P2RX7 et TLR4, notamment rs3751143 (496Glu>Ala) pour le gène P2RX7 et rs4986790 (299Asp>Gly) pour le gène TLR4.Compte tenu des ces résultats que mettent en évidence la relation étroite entre l’efficacité de la chimiothérapie anticancéreuse et un système immunitaire opérationnel, nous avons décidé d'étudier l'effet de ces SNPs, soit sur la survie globale soit sur la survie sans événement, chez des patients atteints de cancer pulmonaire non à petites cellules ou NSCLC (Non-Small Cell Lung Carcinoma) et de cancers de la tête et du cou ou HNSCC (Head and Neck Squamous Cell Carcinoma). De plus, nous avons porté notre attention sur un autre SNP affectant le gène ATG16L1 (Autophagy-related 16-Like 1), notamment rs2241880 (300Thr>Ala) qui compromet l’activité d’un gène fondamental dans le processus d’autophagie.Dans les cancers NSCLC, les allèles mutants "perte de fonction" des gènes ATG16L1, P2RX7 et TLR4 n'affectent pas la survie globale, indépendamment du type de chimiothérapie administrée. Au contraire, les patientes atteintes de HNSCC, portant au moins un allèle "perte de fonction" d’ATG16L1 et TLR4, présentent un taux de survie sans récidive inferieure par rapport aux patients qui présentent un genotype sauvage. Ce travail décrit pour la première fois un biomarqueur prognostique pour ce type de cancer.De plus, nous avons pu définir, par génotypage à haut débit, une signature de SNPs prédictive de la réponse à la chimiothérapie neoadjuvantes à base d'anthracyclines et des taxanes chez les patients atteints de cancer du sein. En particulier, la combinaison des deux paramètres clinicopathologiques classiques (âge lors du diagnostic et récepteur aux œstrogènes) avec les génotypes rs1076669 du gène ECE1 (Endothelin Converting Enzyme 1; 341Thr>Ile) et rs2277413 du gène PZP (Pregnancy-Zone Protein; 813Val>Ala) a permis de définir trois grandes catégories des patients et leur probabilité respective d'atteindre la réponse complète pathologique après traitement.L'identification de nouveaux biomarqueurs associés à une absence/diminution de réponse à la chimiothérapie apparaît critique pour choisir des alternatives thérapeutiques appropriées et éviter les effets secondaires indésirables chez les non-répondeurs
Successful chemotherapeutics can induce a type of tumour cell death that is immunogenic, implying that patient’s dying cancer cells function as a therapeutic vaccine and elicit an anti-tumour immune response that controls the residual disease. The three main hallmarks of immunogenic cell death (ICD) are the pre-apoptotic exposure of calreticulin (CRT) on the cell surface, the autophagy-dependent secretion of ATP during the blebbing phase of apoptosis and the post-apoptotic release of the chromatin-binding non-histone protein high mobility group B1 (HMGB1). CRT, ATP and HMGB1 interact with CD91, purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) and Toll-like receptor 4 (TLR4), respectively, on the surface of dendritic cells (DCs), thus promoting the engulfment of dying cells, the production of IL-1β and the cross-presentation of tumour-associated antigens to T cells, respectively.Our laboratory has demonstrated that adjuvant chemotherapy exhibits a reduced efficacy in breast and colorectal cancer patients bearing single-nucleotide polymorphisms (SNPs) that compromise the function of P2RX7 or TLR4, such as rs3751143 in P2RX7 (Glu496Ala) and rs4986790 in TLR4 (Asp299Gly).Driven by these results, underpinning the intimate relationship between the success of anti-cancer chemotherapy and an operational immune system, we decided to investigate the effect of these SNPs on disease outcome among non-small cell lung carcinoma (NSCLC) and head and neck squamous cell carcinoma (HNSCC) patients. Additionally, we focused our attention on a SNP in autophagy related 16-like 1 (ATG16L1), namely rs2241880 (Thr300Ala), which compromises the activity of one pivotal autophagic gene. In NSCLC patients, loss-of-function ATG16L1, P2RX7 and TLR4 alleles do not affect overall survival, irrespective of the administration and type of chemotherapy. Conversely, HNSCC patients bearing at least one loss-of-function ATG16L1 or TLR4 allele exhibit a reduced disease-free survival when compared to their wild-type counterparts. This is the first report highlighting a putative prognostic biomarker for this malignancy. Furthermore, taking advantage of a high throughput genotyping study, we delineated a SNP-based signature that predicts the response of breast cancer patients to anthracycline- and taxane-based neoadjuvant chemotherapy. Particularly, the combination of two classical clinicophatological parameters (age at diagnosis and estrogen receptor) and genotype at the ECE1 (rs1076669 Thr341Ile) and PZP (rs2277413 Val813Ala) loci allowed us to define three broad categories with a correspondent probability of achieving pathological complete response. The identification of new biomarkers associated with a reduced/absent response to chemotherapy appears critical for selecting appropriate therapeutic alternatives, and avoiding undesired side effects among non-responders

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Hanoteau, Aurélie. "Chemotherapy potentiates immune responses against murine tumors". Doctoral thesis, Universite Libre de Bruxelles, 2016. https://dipot.ulb.ac.be/dspace/bitstream/2013/231745/5/Thesis.pdf.

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There is increasing evidence that the effect of chemotherapy on tumor rejection is not cell autonomous but relies on the immune system. Indeed, several reports have shown that human and murine tumors respond to chemotherapeutic agents more efficiently when the host immune system is intact. In particular, we have shown that cyclophosphamide treatment of DBA/2 mice bearing P815 mastocytoma induces rejection and long term protection in a CD4- and CD8-dependent manner. We used this tumor model, as it is poorly immunogenic, expresses tumor-associated P1A and tumor-specific P1E antigens, encoded by germline and mutated genes, respectively, and allows the identification of some tumor-specific CD8+ T cells.We have previously reported that tumor regression correlates with selective infiltration of CD8+ T cells specific for P1E/H-2Kd antigen in tumor bed upon cyclophosphamide treatment. Unexpectedly, the proportion of CD8+ T cells specific for the tumor-associated antigen P1A in the context of H-2Ld decreases concomitantly, indicating that cyclophosphamide alters the repertoire of CD8+ T cells recognizing tumor antigens. Using P1A KO mice, we found that preferential activation of CD8+ T cells to P1E is not solely due to thymic negative selection. The major role of “mutated” antigens in tumor resistance has been recently highlighted in humans and raises an interesting question about the immune mechanisms of tumor rejection. Additionally to its effect on the specific immune response, cyclophosphamide promotes tumor infiltration by effector memory (P1E/H-2Kd)+ CD8+ T cells which are characterized by higher expression of KLRG1 and Eomes. Our data point to a role of IL-15 and type 1 IFNs for their development, as increased levels of IL-15 and IRF7 were measured in tumor after cyclophosphamide. IFNAR1 blockade interferes with the tumor rejection in 50% of mice and decreases the (P1E/H-2Kd)+ CD8+ T cell infiltration induced by cyclophosphamide, suggesting a role of this cytokine in the expansion and/or recruitment of (P1E/H-2Kd)+ CD8+ T cells in vivo.Altogether, our results suggest that type 1 IFNs and IL-15 induced after cyclophosphamide promote the reprogramming of CD8+ T cells specific for the “mutated” P1E/H-2Kd antigen into effector memory lymphocytes.
Option Biologie moléculaire du Doctorat en Sciences
info:eu-repo/semantics/nonPublished

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Chen, Danny. "Approaches to improve efficacy of cancer chemotherapy /". The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486463321624467.

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Roca-Alonso, Laura. "MicroRNA implications in chemotherapy-induced cardiac toxicity". Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24960.

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The use of anthracyclines such as doxorubicin (DOX) has improved mortality and morbidity in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity typically progresses to heart failure (HF). The knowledge of the mechanisms underlying DOX-related cardiac dysfunction is currently limited, hampering the development of cardioprotective strategies. MicroRNAs (miRNAs) are gene expression regulators that play potent roles in both cardiovascular disease and cancer. We wished to investigate DOX-induced changes in cardiac miRNA expression and the potential alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX injury, either via acute administration to cardiomyocytes in vitro or chronic exposure in vivo, and compared to miRNA profiles from infarcted hearts. We identified an overlapping down-regulation of several members of the miR-30 family. Subsequent experimental validation of a bioinformatically predicted subset of target genes allowed us to confirm four novel miR-30 targets: β1- and β2-adrenoceptors (β1AR, β2AR), Gi alpha 2 (Giα-2) and the pro-apoptotic gene BNIP3L, all of which are essential in cardiomyocytes. The implications of the β-adrenergic pathway in HF are extensively described. Importantly, we show a preferential βAR inhibition by miR-30, having a β-blocker like effect. Additionally, we demonstrate that high miR-30 levels are protective against DOX insults and correlate with lower reactive oxygen species generation in cardiac cultures. Upstream of these mechanisms, we describe the transcription factor GATA-6 to be involved in mediating DOX-induced miR-30 down-regulation. Finally, when assessing the implications of miR-30 in breast cancer, we observed an inverse correlation between miR-30 expression levels and breast cancer cell migration in vitro. Moreover, bioinformatic analyses revealed reduced miR-30 levels in breast cancer patients. Taken together, our findings encourage a potential translational use for miR-30 as an early biomarker as well as a therapeutic strategy, combining a cardioprotective action with pleiotropic anti-cancer effects.

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