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1
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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Prytz, Anna, and 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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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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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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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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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-répondeursSuccessful 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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Jackson, Trachette L. "Mathematical models in two-step cancer chemotherapy /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/5730.
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Sims, Margaret Alison. "Azoreductases in cancer therapy." Thesis, Open University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261397.
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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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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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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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Hartman, J. E. M. "Motor performance following chemotherapy for childhood cancer." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2009. http://hdl.handle.net/1765/14636.
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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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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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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 ScienceDepartment 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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Berglund, Åke. "Optimisation of Chemotherapy Treatment in Advanced Colorectal Cancer." Doctoral thesis, Uppsala University, Department of Oncology, Radiology and Clinical Immunology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2609.
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Colorectal cancer is one of the most common malignant diseases in Sweden – more than 5000 new cases are diagnosed each year. The overall five-year survival is about 60% and in cases of recurrence the prognosis is poor.
In a phase III study in advanced colorectal cancer the response rate was doubled when 5-FU was given as a bolus injection versus as a short infusion. The toxicity was similar and time to progression was longer in the injection group. However, overall survival was not significantly different. Dose-effect relationships of 5-FU were studied in another phase III study recruiting 312 patients. A decrease from 500 mg/m2 to 400 mg/m2 worsened the treatment results. A low incidence of severe toxicity was seen in both groups. An increase to 600 mg/m2 worsened the toxicity without any improvement of the results.
A cytotoxic drug sensitivity test in different tumour types, mainly gastrointestinal cancer, poorly predicted treatment outcome in a phase II study.
The conventional Nordic Flv regimen was split in a phase I/II trial. An escalation of dose was possible and the response rate was 20%.
Thymidylate synthase (TS) and the gene expression of p53 were investigated by immunohistochemical technique in the primary tumours of 132 patients. None of the markers predicted the later palliative chemotherapy result. However, TS significantly predicted time to recurrence.
Serum markers were analysed before and during FLv treatment to early predict outcomes among 87 patients. TPS is promising, both as a predictive marker before start of treatment and after a short period of treatment. In the same setting, CEA had lower predictive value. S-VEGF and S-bFGF did not yield any prognostic information of later outcome. In all studies B-haemoglobin values, performance status and subjective response were strong markers, both for prediction of objective response and for survival.
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Tohnai, Iwai. "Chemotherapy using Intra-Arterial Infusion for Oral Cancer." Nagoya University School of Medicine, 2006. http://hdl.handle.net/2237/6962.
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Beyer, Kathryn. "Depression in patients with cancer receiving adjuvant chemotherapy." University of Southern Queensland, Faculty of Sciences, 2009. http://eprints.usq.edu.au/archive/00006177/.
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This simple quantitative research investigated whether patients with cancer developed depression whilst receiving adjuvant chemotherapy, and whether there was a particular time in the treatment cycle that it was likely to develop. A longitudinal survey method was chosen and the instrument of use was the Beck Depression Inventory II (BDI-II). The content of this survey include factors that reflect negative attitudes towards self, performance impairment and somatic disturbances as well as general factors of depression. Twenty-six participants were given the BDI-II, and asked to report on side effects that they had experienced every two weeks whilst they were receiving chemotherapy. The study took place in two regional oncology clinics. This report demonstrates that, patients can develop depression whilst receiving adjuvant chemotherapy. The study revealed that the 5th fortnight into a patient’s chemotherapy treatment was a more vulnerable point in their treatment to develop depression. Descriptive analysis illustrated that more females than males suffered depression and that those receiving treatment for breast cancer were more likely to develop depression. Correlation statistics demonstrated a relationship between fatigue and depressive symptoms. There was no statistically significant correlation between the number of side effects experienced by participants and depression. In summary, the findings suggest that patients were more vulnerable to developing depression around the 5th fortnight of their chemotherapy cycle. This research has demonstrated throughout that depression does occur in patients receiving adjuvant chemotherapy and that female patients are more likely to develop depression than males. Due to the small sample size though, the results were not statistically significant. The findings from this research could provide direction for more thorough studies in the future. The style of reporting used throughout this thesis has been the Harvard referencing style to ensure compliance with the university requirements and to maintain consistency.
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Anderson, Judith Anne 1949. "Sleep and fatigue in cancer patients, receiving chemotherapy." Thesis, The University of Arizona, 1994. http://hdl.handle.net/10150/278425.
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A descriptive correlational study was conducted to examine the relationship between sleep characteristics and fatigue in persons with cancer, receiving chemotherapy. Twenty-five adult patients, receiving chemotherapy in outpatient and inpatient hospital settings, participated in the study. The Verran and Snyder-Halpern (VAS) Sleep Scale (1989) was used to measure the sleep characteristics of subjects and the Piper Fatigue Scale (PFS) (1992) was used to measure characteristics of fatigue. Demographic data were also collected. Significant relationships (p 0.05) were found between the dimension of Sleep Disturbance and the fatigue dimensions of Sensory, Temporal, and Affective. A positive correlation was demonstrated between Sleep Supplementation and the Temporal dimension of fatigue. Gender differences were evident in the relationships between sleep and fatigue. Nurses are in a unique position to assist patients in coping with the side-effects of cancer treatment. Patient education can assist patients in understanding the limitations and self-care actions appropriate for sleep and fatigue.
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Bray, Johanne S. "Pharmacogenetic influences on the chemotherapy of breast cancer." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506606.
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Rendle, P. M. "The preparation of possible prodrugs for cancer chemotherapy." Thesis, University of Canterbury. Chemistry, 1997. http://hdl.handle.net/10092/7259.
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This thesis concerns the design and preparation of compounds which are relevant to a new strategy for the selective chemotherapeutic treatment of tumour cells. These bridged polycyclic compounds are prepared by Diels-Alder chemistry involving cyclic dienes. The bridge is to be cleaved at the cancer site by tumour-selective chemistry acting on an appropriate trigger. This activation of a low toxicity 'prodrug' results in the formation of a planar, aromatic structure which is a characteristic of known anti-cancer drugs (intercalating agents).
The crucial step in the organic synthesis of these potential prodrugs is a DielsAlder reaction involving two classes of diene, 1-(methylthio)isobenzofurans and
pyranones, with various dienophiles. Examination of this step started with the reaction of 1,1-bis(methylthio)ethene with various pyranones. Stable adducts were isolated from its reaction with methyl coumalate and a benzopyranone; but only substituted
carbazoles were observed from the reaction with pyrano[3,4-b]indol-3-ones. An investigation into the thermal stability of the isolated adducts resulted in the observation of an unusual [1,]-methylthio migration. In comparison to 1, 1 bis(methylthio)ethene, 1-(methylthio)-1-(p-tolylsulfonyl)ethene was observed to have lower reactivity and regioselectivity upon reaction with electron-deficient
pyranones. The resulting adducts were unstable due to the facile elimination of
p-toluenesulfinic acid and only aromatic products were isolated. Diels-Alder adducts were isolated from the reaction of 1-(methylthio)-1-(p-tolylsulfonyl)ethene with
1-(methylthio)isobenzofurans, but they were of low stability and of mixed regio- and stereo- chemistries. The reaction of arynes with 1-(methylthio)isobenzofurans was also investigated. The Diels-Alder reaction between 3,4-didehydropyridine and a protected
1-(methylthio)isobenzofuran resulted in the preparation of a precursor of a tricyclic hetero-aromatic compound, namely the known biologically active compound, 2-azaanthraquinone.
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Newton, C. "Clinical resistance to platinum chemotherapy in ovarian cancer." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/1446312/.
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Platinum drugs are the most active agents in ovarian cancer. Their cytotoxicty results from DNA crosslinking. High tumour response rates are seen, but 80 % of patients relapse. Major mechanisms of platinum resistance in patients remain to be established. We have studied DNA interstrand crosslinking and its repair in response to ex vivo treatment with cisplatin in forty patients with ovarian cancer using the single cell gel electrophoresis (comet) assay. Tumour cells from resected tumours or tumour and mesothelial cells from ascites were obtained from chemonaive patients and those relapsing after platinum-based therapy. The average percent decrease in tail moment at the peak of crosslinking was 61.1% 9.25 in 34 pre-chemotherapy patient samples following treatment with lOOuM cisplatin. In 14 post-chemotherapy patient samples it was 58.1% 9.94. The average percentage repair at 24 hours was 3.6% 18.89 in pre- chemotherapy patients and 44.6% 43.4 for post-chemotherapy patients (p < 0.001). In 6 paired samples, before and after chemotherapy the average percentage repair at 24 hours was 7.2% 12.64 increasing to 69.5% 23.42 after chemotherapy. Differences in cell cycling, and cell signalling gene expression levels using microarray analysis was found, between pre- and post-chemotherapy patients. Real time PCR was also used to investigate the levels of ERCC1 (excision-related cross complementation group 1) in 3 of these paired patient samples, which was found to be increased by an average of 14.4% +/-0.8% in 3 post-chemotherapy samples. In ten pre-chemotherapy and seven post-chemotherapy patient tumours incubated ex vivo with 50uM melphalan, the percent decrease in tail moment at the peak of crosslinking was 41.4+11.2, and 44.6 7.6, respectively. 24 hours later the percentage repair was 3.1 .25.6 for untreated and 2.8 26.3 for treated tumours. In conclusion, repair of DNA interstrand crosslinks appears to be an important mechanism of clinical platinum resistance in ovarian cancer. Repair of melphalan crosslinks is unaffected.
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Adlard, Julian Weldon. "Colorectal cancer : predictive factors for response to chemotherapy." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415610.
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Dive, C. "Flow cytoenzymology with special reference to cancer chemotherapy." Thesis, Open University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384585.
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Zhao, Liang. "Evaluation of combination cancer chemotherapy theory and practice /." Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1070398620.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xvii, 158 p.; also includes graphics (some col.) Includes bibliographical references (p. 146-158). Available online via OhioLINK's ETD Center
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Jansen, Catherine E. "Cognitive function in breast cancer patients undergoing chemotherapy." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3261235.
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Zheng, Jenny Huimin. "Regional Cancer Chemotherapy: Drug Penetration and Pharmacokinetic Evaluation." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1392044351.
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Chen, Jun. "Transition Metal Complexes of Nucleosides for Cancer Chemotherapy." University of Dayton / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1461516224.
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Barnes, John George. "Synthesis of agents potentially useful in cancer chemotherapy." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/synthesis-of-agents-potentially-useful-in-cancer-chemotherapy(9ca50dd6-7c8f-4137-93a0-d68b77b596b6).html.
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A range of novel, potent, inhibitors of NAD(P)H quinone oxidoreductase 1 (NQO1) and NAD(P)H quinone oxidoreductase 2 (NQO2) were synthesised. The therapeutic utility of this could be three-fold: 1) Impairing tumour growth.2) Promoting the transient degradation of the p53 tumour suppressor protein in cells can enhance the activity of conventional anti-cancer drugs. 3) For probing the effects of NQO1 or NOQ2 inhibition within cells. The potential inhibitors were classified as three distinct groups based on the core structure, known as the triazoloacridinones (31), imidazoacridinones (131), and 4-hydroxycoumarins (182 - 195, 197 - 210). The syntheses of the triazoloacridinones (31) and imidazoacridinones (131) were achieved through divergent synthetic routes, so that a large variety of compounds could be made quickly, and economically. A selection of these were then modified to increase potency, improve water solubility, and lower toxicity. The final 4-hydroxycoumarin series (183, 190, 192, 199, 201, 215, 216) was first produced using existing methods. Later, a more desirable route was developed using the 'borrowing hydrogen' methodology, to improve upon the efficiency and yield. All three families of compounds were found to contain potent, nanomolar inhibitors of NQO1 and NQO2, which could inhibit the enzymes in cells, at non-toxic concentrations.
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Kirkham, Amy Ashley. "Exercise cardio-protection from chemotherapy for breast cancer." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57056.
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One in nine women in Canada will be diagnosed with breast cancer during their lifetime, yet 88% will live for at least five years after diagnosis. Cardiovascular disease has become the most common cause of death of older breast cancer survivors, and breast cancer survivors are more likely to die of cardiovascular disease than women who have not had breast cancer. One of the contributing factors to the increased cardiovascular morbidity and mortality is anthracycline chemotherapy-related cardiotoxicity, or damage to the myocardium. The need for balance of oncological efficacy with cardiotoxicity of anthracycline chemotherapy has driven the active investigation of cardio-protective strategies. Exercise, an accessible and inexpensive intervention with numerous other health benefits, has demonstrated efficacy for attenuating cardiotoxicity in numerous preclinical (i.e. animal model) studies; a finding yet to be confirmed by clinical research. This dissertation investigated the potential for exercise cardio-protection from anthracycline chemotherapy in women diagnosed with breast cancer in three studies. The primary findings are: 1) during anthracycline treatment, adherence to supervised exercise training following the guidelines for cancer survivors varies widely; 2) the primary reason for withdrawal, missed exercise sessions, and non-adherence to prescribed intensity and/or duration was treatment-related symptoms; 3) despite low and variable adherence, women who enrolled in an exercise training program during anthracycline chemotherapy for breast cancer did not experience a clinically relevant deterioration of echocardiography-derived systolic global longitudinal strain or strain rate, which are both established predictive markers of cardiotoxicity; 4) global longitudinal strain has excellent intra-observer reliability and is consistently measurable in breast cancer patients, making it an excellent option for an outcome measure to assess cardio-protection; 5) performance of a single vigorous intensity aerobic exercise bout performed 24 hours prior to anthracycline treatment attenuates the acute NT-proBNP myocardial injury marker response to the first treatment, and alters hemodynamic regulation and cardiac structure after completion of treatment, but has no effect on longitudinal strain or strain rate or treatment symptoms. Overall this dissertation provides proof-of-principal for exercise cardio-protection, and contributes novel findings regarding exercise prescription and outcome measure assessment for future exercise cardio-protection studies during anthracycline treatment for breast cancer.Medicine, Faculty of
Graduate
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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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Zhang, Qian, and 张茜. "Retrospective analysis of bevacizumab and cetuximab in advanced Asian colorectal cancer patients." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/209506.
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Colorectal cancer is a serious health problem that has concerned people for decades. In Hong Kong, it is the most common cancer and the second leading cause of death. Among colorectal cancer patients, around 40-50% of them will develop metastatic disease. Chemotherapy is playing an important role all the time in the treatment of advanced colorectal cancer. In the past decade, the application of targeted therapies in treatment has largely improved efficacy and prolonged survival. Bevacizumab and cetuximab are two commonly used targeted agents in daily clinical practice of Hong Kong. Since multiple clinical trials have studied bevacizumab and cetuximab in combination with other chemotherapies, limited data is available in Asian patients. Therefore, we conduct three 5-year retrospective analyses based on patients received treatment in Hong Kong Queen Mary Hospital, to investigate the clinical efficacy and toxicity of those two drugs. The first study examined the use of bevacizumab in treating KRAS mutated type patients. We found the efficacy and results were consistent with historical data. In the next analysis of cetuximab, comparable data were shown which suggested the consistency with previous studies. The last study is aim to compare bevacizumab and cetuximab in previously untreated wild-type KRAS patients. Identical response rates, progression-free survival and overall survival were finally reported.published_or_final_version
Medicine
Master
Master of Philosophy
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Yan, Tristan Dongbo Clinical School St George Hospital Faculty of Medicine UNSW. "Cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal surface malignancy." Awarded by:University of New South Wales. Clinical School - St George Hospital, 2007. http://handle.unsw.edu.au/1959.4/40538.
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In the past, patients with peritoneal surface malignancy were considered incurable and were only offered palliative treatments. However, in a substantial number of patients, disease progression that is isolated to peritoneum may occur. It has been realised that elimination of peritoneal surface tumours may have an impact on the survival of these cancer patients, in whom a prominent cause of death is peritoneal carcinomatosis. The focus of this PhD. thesis is on the combined treatment of cytoreductive surgery and perioperative intrapersonal chemotherapy for diffuse malignant peritoneal mesothelioma, pseudomyxoma peritonei, colorectal peritoneal carcinomatosis and resectable gastric cancer. Section one describes the major principles of management for peritoneal surface malignancy, covering the historical perspectives, the treatment rationales and the learning curve associated with the combined procedure. Section two is devoted to peritoneal mesothelioma, in trying to examine this disease from its clinical, radiologic and histopathologic aspects. A radiologic classification and a histopathologic staging system for this disease are proposed. In section three, the results of the combined treatment for pseudomyxoma peritonei are presented, including a systematic review of the literature, a case series of 50 patients from our Australian centre and a treatment failure analysis of 402 patients from the Washington Cancer Institute. These studies suggest that a disease-free state is important for long-term survival for patients with pseudomyxoma peritonei. In section four, the current evidence on the combined treatment for colorectaI peritoneal carcinomatosis is demonstrated by conducting a systematic review of the literature and survival and perioperative outcome analyses of two separate patient cohorts. These results suggest that the combined treatment is associated with an improved survival, as compared with historical controls. In the last section, a metaanalysis of the randomised controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer shows that a significant improvement in survival is associated with hyperthermic intraoperative intraperitoneal chemotherapy alone or in combination with early postoperative intraperitoneal chemotherapy.
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High, Rachel. "Detection of Chemotherapy-Induced Apoptosis in Human Breast Cancer." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/578931.
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Caspase-cleaved keratin 18 (K18) is used as a biomarker of apoptosis to measure chemotherapy-induced cell death. The M30-FITC antibody can be used as a method of detection for caspase-cleaved K18, giving it potential as a prognostic and predictive tool in cancer treatment. This study tests the M30-FITC antibody for use with the human breast cancer cell lines MCF7, SKBR3, and MDA-MB-231 in flow cytometry, with the goal of optimizing the M30-FITC assay for use in human whole blood. The assay was evaluated for use with two different apoptotic pathways: first induced by the chemotherapy docetaxel (Taxotere), and then by the tumor inhibitor staurosporine. Analysis indicates that the M30-FITC antibody requires a specific caspase cleavage product to be produced during apoptosis, which the mechanism of docetaxel-induced apoptosis (mitotic catastrophe) does not appear to produce. Staurosporine treatment appears to induce apoptosis in a manner compatible for use with the M30 antibody, and is sufficient to induce apoptosis in MCF7, SKBR3, and MDA-MB-231. These treated cells are also suitably detected in spiked human whole blood, indicating the potential for clinical relevance of the assay.
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Berrieman, Helen Katherine. "Resistance to chemotherapy in non-small cell lung cancer." Thesis, University of Hull, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415803.
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Evert, Jasmine. "Molecular studies of radiotherapy and chemotherapy in colorectal cancer." Doctoral thesis, Örebro universitet, Institutionen för hälsovetenskap och medicin, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-43635.
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Barnawi, Ibrahim. "Mechanisms of apoptosis resistance in chemotherapy-resistant cancer cells." Thesis, University of Reading, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627931.
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Most chemotherapy drugs work through the induction of apoptosis in tumour cells. Mutations in apoptotic pathways, notably p53 and Bcl-2, are common in cancer and associated with increased resistance to apoptosis and therefore to chemotherapy. The sensitivity of two types of cells have been compared, A 172 human glioblastoma cells and MDA-MB-23l human breast cancer cells, for their sensitivity to the chemotherapy drugs cisplatin, doxorubicin, gemcitabine, vincristine and temozolomide. Data shows that there were differences in the sensitivity of breast cancer and glioma cells to a variety of chemotherapy drugs. There were differences in nitric oxide synthase (NOS) expression between the two different types of cancer cells and yet a role was not observed for nitric oxide in changing the expression of the Bcl-2 family of proteins (both pro- or antiapoptotic). Additionally, NOS expression changed following treatment with chemotherapy drugs, suggesting that this may be the mechanism by which the cells become resistant.
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Khongkow, Pasarat. "The role of FOXM1 in breast cancer chemotherapy resistance." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/42884.
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Resistance to chemotherapeutic agents is the main obstacle to the effective breast cancer management. Therefore, it is important to elucidate the molecular mechanisms of chemoresistance and develop novel therapeutic strategies in order to overcome drug resistance. In this work, I found that FOXM1 is a critical mediator of epirubicin and paclitaxel resistance in MCF-7 breast cancer cell lines. FOXM1 expression was upregulated in both epirubicin resistant MCF-7 (MCF-7 EpiR) and paclitaxel resistant MCF-7 (MCF-7 TaxR) cells compared to sensitive MCF-7 cells. Interestingly, its depletion dramatically impaired the clonogenic survival and significantly induced cellular senescence in the resistant cells. In addition, I identified two novel downstream FOXM1 targets, NBS1 and KIF20A, involved in epirubicin and paclitaxel resistance, respectively. Firstly, I found that FOXM1 transcriptionally regulated NBS1 expression to modulate HR-mediated DSB repair and epirubicin resistance. Overexpression of FOXM1 and NBS1 lead to the enhancement of HR efficiency to eliminate epirubicin-induced DNA damage. Conversely, similar to FOXM1, depletion of NBS1 also sensitised both MCF-7 and MCF-7 EpiR cells to epirubicin by inducing cellular senescence. Secondly, I identified the mitotic kinesin KIF20A as a direct downstream target of FOXM1, participating in the mitotic spindle formation and paclitaxel resistance. Depletion of KIF20A caused mitotic spindle abnormalities, inhibition of cell growth as well as the induction of senescent cells in both MCF-7 and MCF-7 TaxR cells. Consistently, immunohistochemical analysis of breast cancer patient samples revealed that high expression levels of FOXM1, NBS1 and KIF20A are strongly correlated with poor prognosis in breast cancer, supporting a physiological role of FOXM1 and its novel targets in genotoxic drug resistance. Collectively, these findings suggests that FOXM1 and its targets, NBS1 and KIF20A, could be reliable prognostic markers for monitoring treatment efficiency as well as promising targets for therapeutic intervention to overcome epirubicin and paclitaxel resistance in breast cancer.
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Weinberg, Brent D. "Intratumoral Chemotherapy for Liver Cancer Using Biodegradable Polymer Implants." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1176749922.
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Shirai, Takako. "Primary chemotherapy patterns for ovarian cancer treatment in Japan." Kyoto University, 2010. http://hdl.handle.net/2433/120581.
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Garnier, Nicolas. "Mechanisms of action of the novel anti-cancer organic arsenical darinaparsin (ZIO-101, S-dimethylarsino- glutathione, Dar) in cancer cells." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119553.
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Arsenic trioxide (ATO) is a successful treatment option for Acute Promyelocytic Leukemia (APL), but other cancers remain mildly sensitive to ATO at clinically achievable doses. Moreover, APL cells can develop resistance to ATO. It has been shown that resistance to ATO and/or moderate sensitivity correlates with either modulation of arsenic transport or increased expression of cytoprotective enzymes. Darinaparsin (S-dimethylarsino-GSH; Dar) is a significantly more potent apoptosis-inducing arsenical than ATO in various malignant cell lines and in APL patient blasts. It also has a maximum tolerated dose that is 35-fold higher than ATO. Interestingly, ATO-resistant APL cells are sensitive to Dar. Dar accumulates in the cell to a greater extent that ATO, which led us to the hypothesis that Dar import might also contribute to its enhanced efficacy. We show that both ATO and Dar induce the expression of the cystine importer xCT. We found that extracellular thiols inhibit Dar intracellular accumulation, as well as apoptosis. Thus, we hypothesized that thiols can prevent Dar import. GSH itself is not imported in the cell, so we thought it unlikely that Dar would enter the cell without being somehow modified. Structural analysis of Dar reveals putative break-down products: dimethylarsino-cysteine (DMAC), dimethylarsenic III (DMA III) and dimethylarsenic V (DMA V). We show that treatment with DMA III and DMA V does not lead to intracellular accumulation of arsenic, and correlates with their inability to induce cell death. However, DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, G2/M arrest and cell death. As with Dar, thiols can inhibit DMAC effects. Therefore, we hypothesize that Dar gets transformed extracellularly into DMAC, which is imported via xCT or another cystine/cysteine importing system. We validated this hypothesis by shRNA knock-down of xCT. We also hypothesized that the increased cytotoxicity of Dar may be due to a decreased cytoprotective response, and therefore studied the expression of stress response enzymes after ATO and Dar treatment. We observed a lack of expression of one of the nuclear factor (erythroid-derived 2)-like 2 phase-II (NRF2)-dependant detoxifying enzymes, heme-oxygenase 1 (HO-1), after Dar treatment, compared to ATO. We found that Dar does not recruit NRF2 to the HO-1 promoter's antioxidant response elements (AREs). We also found that Dar treatment did not recruit Brahma-related gene 1 (BRG1) coactivator to HO-1 AREs. BRG1 localization has been linked to cell cycle and we found that ATO induces a G1 arrest while Dar induces a G2/M arrest. Importantly, we found the Dar induced G2/M arrest to correlate with hyper-phosphorylated BRG1 causing it to be excluded from the chromatin, preventing HO-1 induction. In order to elucidate the cytoprotective effect of HO-1, we examined the cytotoxicity of ATO and Dar following pharmacological or genetic inhibition HO-1. We showed that inhibition of HO-1 increased the toxicity of ATO, but had no effect on Dar-induced apoptosis. We also showed that BRG1 silenced NB4 cells exhibit reduced HO-1 expression in response to ATO, and are more sensitive to ATO-induced apoptosis. We conclude that the lack of HO-1 activation is partially responsible for Dar's enhanced anti-tumor properties. Cells respond to arsenicals by increasing cystine uptake and HO-1 expression, which leads to protection against ATO but hypersensitivity to Dar.Le trioxyde d'arsenic (ATO) est un traitement efficace contre la leucémie promyelocytaire aigue (APL), mais les autres types de cancers y sont peu sensibles à des doses utilisables en clinique. De plus, les cellules APL peuvent développer une résistance contre ATO. La résistance contre ATO et/ou une sensibilité modérée est associée à la modulation du transport de l'arsenic ou à une augmentation de l'expression d'enzymes cytoprotectrices. Darinaparsin (S-dimethylarsino-GSH; Dar) est un dérivé d'arsenic, inducteur d'apoptose, plus puissant qu'ATO dans plusieurs lignées cellulaire malignes et dans des blasts de patient APL. La dose maximum tolérée pour Dar est 35 fois plus élevée par rapport à ATO. Les cellules APL résistantes à ATO sont sensibles à Dar. Dar s'accumule plus dans la cellule qu'ATO, ce qui nous a menés vers l'hypothèse selon laquelle l'import de Dar contribue à son efficacité élevée. Nous montrons qu'ATO et Dar induisent l'expression de l'importateur de cystine xCT. Nous avons trouvé que des thiols extracellulaires inhibent l'accumulation intracellulaire de Dar, ainsi que l'apoptose. Ainsi, nous avons formulé l'hypothèse selon laquelle les thiols peuvent empêcher l'import de Dar. GSH en tant que telle n'est pas importée dans la cellule, nous avons donc pensé qu'il serait improbable que Dar entre dans la cellule sans être modifié. L'analyse structurelle de Dar révèle des produits potentiels de dégradation : dimethylarsino-cysteine (DMAC), dimethylarsenic III (DMA III) et dimethylarsenic V (DMA V). Nous montrons que DMA III et DMA V ne conduisent pas à l'accumulation intracellulaire d'arsenic, ce qui correspond à leur inaptitude à induire la mort cellulaire. Cependant, DMAC est très similaire en terme d'accumulation intracellulaire d'arsenic, arrêt du cycle cellulaire en phase G2/M et mort cellulaire. Tout comme avec Dar, les thiols peuvent inhiber les effets de DMAC. Ainsi, nous formulons l'hypothèse selon laquelle Dar est transformé à l'extérieur de la cellule en DMAC, qui est importé via xCT ou d'autres systèmes d'import de la cysteine/cystine. Nous avons validé cette hypothèse grâce à une atténuation de l'expression de xCT par shRNA. Nous avons également formulé l'hypothèse selon laquelle la cytotoxicité accrue de Dar pourrait être due à une réponse cytoprotectrice décrue, et avons donc étudié l'expression des enzymes de réponse au stress. Nous avons observé un manque d'expression d'une des enzymes de détoxification dépendantes du facteur nucléaire erythroid-derived 2-like 2 phase-II (NRF2), heme-oxygenase 1 (HO-1), après le traitement avec Dar, en comparaison avec ATO. Nous montrons que Dar ne recrute pas NRF2 à l'élément de réponse antioxydante (ARE) du promoteur de HO-1. Nous montrons aussi que le traitement avec Dar ne recrute pas le co-activateur Brahma-related gene 1 (BRG1) au ARE de HO-1. La localisation de BRG1 a été reliée au cycle cellulaire et nous avons montré que ATO induit un arrêt en phase G1 tandis que Dar induit un arrêt en phase G2/M. Nous avons montré qu'il y a une corrélation entre l'arrêt en phase G2/M induit par Dar et une hyper-phosphorylation de BRG1 induisant son exclusion de la chromatine, empêchant ainsi l'induction de HO-1. De façon à élucider l'effet cytoprotectif de HO-1, nous avons examiné la cytotoxicité de ATO et Dar après une inhibition pharmacologique ou génétique de HO-1. Nous avons montré que l'inhibition de HO-1 augmente la toxicité d'ATO mais pas celle de Dar. Nous avons également montré que des cellules NB4 n'exprimant plus BRG1 ont une expression réduite d'HO-1 en réponse à ATO, et sont plus sensibles à l'apoptose induite par ATO. Nous concluons que le manque d'activation de HO-1 est partiellement responsable de l'efficacité anti-tumorale accrue de Dar. Les cellules répondent à l'arsenic en augmentant l'import de la cystine et l'expression d'HO-1, ce qui conduit à une protection face à ATO mais à une hypersensibilité à Dar.
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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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Petrovski, Andrei. "An application of genetic algorithms to chemotherapy treatment." Thesis, Robert Gordon University, 1998. http://hdl.handle.net/10059/1259.
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The present work investigates methods for optimising cancer chemotherapy within the bounds of clinical acceptability and making this optimisation easily accessible to oncologists. Clinical oncologists wish to be able to improve existing treatment regimens in a systematic, effective and reliable way. In order to satisfy these requirements a novel approach to chemotherapy optimisation has been developed, which utilises Genetic Algorithms in an intelligent search process for good chemotherapy treatments. The following chapters consequently address various issues related to this approach. Chapter 1 gives some biomedical background to the problem of cancer and its treatment. The complexity of the cancer phenomenon, as well as the multi-variable and multi-constrained nature of chemotherapy treatment, strongly support the use of mathematical modelling for predicting and controlling the development of cancer. Some existing mathematical models, which describe the proliferation process of cancerous cells and the effect of anti-cancer drugs on this process, are presented in Chapter 2. Having mentioned the control of cancer development, the relevance of optimisation and optimal control theory becomes evident for achieving the optimal treatment outcome subject to the constraints of cancer chemotherapy. A survey of traditional optimisation methods applicable to the problem under investigation is given in Chapter 3 with the conclusion that the constraints imposed on cancer chemotherapy and general non-linearity of the optimisation functionals associated with the objectives of cancer treatment often make these methods of optimisation ineffective. Contrariwise, Genetic Algorithms (GAs), featuring the methods of evolutionary search and optimisation, have recently demonstrated in many practical situations an ability to quickly discover useful solutions to highly-constrained, irregular and discontinuous problems that have been difficult to solve by traditional optimisation methods. Chapter 4 presents the essence of Genetic Algorithms, as well as their salient features and properties, and prepares the ground for the utilisation of Genetic Algorithms for optimising cancer chemotherapy treatment. The particulars of chemotherapy optimisation using Genetic Algorithms are given in Chapter 5 and Chapter 6, which present the original work of this thesis. In Chapter 5 the optimisation problem of single-drug chemotherapy is formulated as a search task and solved by several numerical methods. The results obtained from different optimisation methods are used to assess the quality of the GA solution and the effectiveness of Genetic Algorithms as a whole. Also, in Chapter 5 a new approach to tuning GA factors is developed, whereby the optimisation performance of Genetic Algorithms can be significantly improved. This approach is based on statistical inference about the significance of GA factors and on regression analysis of the GA performance. Being less computationally intensive compared to the existing methods of GA factor adjusting, the newly developed approach often gives better tuning results. Chapter 6 deals with the optimisation of multi-drug chemotherapy, which is a more practical and challenging problem. Its practicality can be explained by oncologists' preferences to administer anti-cancer drugs in various combinations in order to better cope with the occurrence of drug resistant cells. However, the imposition of strict toxicity constraints on combining various anticancer drugs together, makes the optimisation problem of multi-drug chemotherapy very difficult to solve, especially when complex treatment objectives are considered. Nevertheless, the experimental results of Chapter 6 demonstrate that this problem is tractable to Genetic Algorithms, which are capable of finding good chemotherapeutic regimens in different treatment situations. On the basis of these results a decision has been made to encapsulate Genetic Algorithms into an independent optimisation module and to embed this module into a more general and user-oriented environment - the Oncology Workbench. The particulars of this encapsulation and embedding are also given in Chapter 6. Finally, Chapter 7 concludes the present work by summarising the contributions made to the knowledge of the subject treated and by outlining the directions for further investigations. The main contributions are: (1) a novel application of the Genetic Algorithm technique in the field of cancer chemotherapy optimisation, (2) the development of a statistical method for tuning the values of GA factors, and (3) the development of a robust and versatile optimisation utility for a clinically usable decision support system. The latter contribution of this thesis creates an opportunity to widen the application domain of Genetic Algorithms within the field of drug treatments and to allow more clinicians to benefit from utilising the GA optimisation.
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MacPhee, Meaghan. "Stabilized combi-molecules for the treatment of breast cancer." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40846.
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We recently developed a novel strategy termed “combi-targeting” that seeks to design “combi-molecules” which are able to not only block EGFR but to also damage DNA. Previous studies that sought to stabilize triazene based combi-molecules were based on masking the 1,2,3-triazene chain with a 2-acetoxymethylene group, leading to the synthesis of RB24 and RB107. The half-lives of these two molecules proved to be only about 5 minutes longer than their parent triazenes. The novel series of molecules presented herein were designed containing hydrolysable groups to modulate the kinetics of their degradation,. These include vinyl, acetoxymethyloxyl, and p-nitrophenol carbamates. Kinetic studies determined that the vinyl carbamate ZRL2 was the most stable of the series. However, its vinyl counterpart ZRL1 designed to be cleaved by a basic neighbouring group was the least stable. The half-lives of all of the other molecules were significantly longer than that of RB107. Specifically, ZRL1 had a half-life approximately 20 min longer and ZRS1, ZRL4, ZRL5 40-55 min longer. The molecules were designed to release a fluorescent aminoquinazoline, FD105, upon degradation. This allowed us to observe its intracellular release by fluorescent microscopy. ZRL1 generated the highest level of fluorescence and its more stable counterpart, ZRL2, produced levels that were barely detectable. Studies directed at determining the dual EGFR-DNA targeting abilities of the molecules showed that: (a) all of the compounds were capable of blocking the EGFR tyrosine kinase activity in an isolated enzyme assay and in MDAMB468 cells, (b) all of the molecules, except for the most stable compound ZRL2, were capable of inducing dose-dependent DNA damage, and (c) induction of DNA damage was associated with cell cycle arrest in G2/M. Using a growth inhibition assay, it was determined that all of the molecules could: (a) block the growth of MDAMB468 cells and (b) preferentially inhibit the EGFR transfeNous avons récemment mis au point une nouvelle stratégie dénommée “combi-ciblage” : cette stratégie est basée sur des agents appelés “combi-molécules”, capables non seulement de bloquer l’EGFR, mais aussi d’induire des lésions de l’ADN. Des études antérieures réalisées au laboratoire et ayant pour but de masquer la chaîne 1,2,3-triazène de certaines combi-molécules par un groupement 2-acétoxyméthylène afin de les stabiliser ont conduit à l’obtention des composés RB24 et RB107. Ces travaux n’ont toutefois pas permis d’augmenter de manière significative les temps de demi-vie de ces deux molécules, puisqu’ils n’étaient supérieurs que d'environ 5 minutes aux temps de demi-vie des molécules triazéniques initiales. Les nouvelles séries de molécules présentées dans cette thèse contiennent un groupement carbamate hydrolysable permettant d’optimiser leur cinétique de dégradation. D’autres modifications ont été également appliquées, notamment l'ajout de différents groupements tels que des vinyl, acétoxyméthyloxyl, et p-nitrophénol carbamates. Ainsi, les études cinétiques ont montré que le vinyl carbamate ZRL2 est le plus stable de ces séries. En revanche, son homologue vinylique ZRL1, conçu pour être clivé par un groupement basique voisin, s’est avéré être le moins stable avec un temps de demi-vie toutefois supérieur d’environ 20 minutes à celui du RB107. Les temps de demi-vie des autres composés se sont significativement allongés, notamment pour ZRS1, ZRL4, et ZRL5, dont les temps de demi-vie dépassent de 40 à 55 minutes celui du RB107. De plus, ces molécules ont été conçues pour libérer un groupement fluorescent de type aminoquinazoline (FD105) au cours de leur dégradation. Par conséquent, nous pouvons observer leur localisation intracellulaire, de même que leur abondance, par microscopie à fluorescence. Ainsi, ZRL1 génère la plus grande quantité de fluorescence, tandis$
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Matheson, Karen Ann. "Learning needs of cancer patients receiving chemotherapy : patient, nurse, and physician perceptions." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/26133.
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Accurate assessment of educational needs is central to the planning of effective patient education programs. Adult learning theory holds that the more agreement that exists in the educator's and the learner's assessment of learning needs, the higher the probability that effective learning will occur. This descriptive survey was carried out to compare the learning needs of cancer patients receiving chemotherapy as perceived by three groups involved in patient education: nurses, physicians, and patients themselves.
Using the Assessment of Learning Needs Questionnaire (ALNQ) developed by Lauer, Murphy, and Powers (1982) and demographic data questionnaires developed by the researcher, the perceptions of patients' learning needs held by a convenience sample of 20 lymphoma patients, 24 nurses, and ten physicians were studied. Responses to the rating and ranking scales of the ALNQ were analyzed using nonparametric statistical techniques to determine the existence and location of differences in perceptions among the three groups. General comments about patient education and the ALNQ were gathered from the patient group in an interview setting and from the two care giver groups through responses to two open-ended questionnaire items.
Findings revealed that the learning needs of patients undergoing chemotherapy tend to focus on concerns related to the treatment experience, and the knowledge and skills required to cope with the impact of the disease and treatment on their lives. Patients described themselves as most knowledgeable in areas relating to life experience, rather than disease or treatment related areas, and were oriented to survival in their learning needs. The three groups demonstrated considerable similarity in their perceptions of areas problematic to patients and areas in which patients have the most knowledge. However, despite presumed knowledge and expertise in dealing with the concerns of chemotherapy patients, nurses' and physicians' perceptions of patients' learning needs differed from those held by patients. The care givers perceived patients to be more concerned with learning needs related to activities of daily living than patients reported. Implications for nursing practice and education are suggested, and recommendations made for further study.Applied Science, Faculty of
Nursing, School of
Graduate
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Hartmann, Neil Godfried. "Intercalative drugs in cancer chemotherapy : two approaches towards drug development." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292983.
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Petryk, Alicia Ailie. "Magnetic nanoparticle hyperthermia as an adjuvant cancer therapy with chemotherapy." Thesis, Dartmouth College, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3634608.
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Magnetic nanoparticle hyperthermia (mNPH) is an emerging cancer therapy which has shown to be most effective when applied in the adjuvant setting with chemotherapy, radiation or surgery. Although mNPH employs heat as a primary therapeutic modality, conventional heat may not be the only cytotoxic effect. As such, my studies have focused on the mechanism and use of mNPH alone and in conjunction with cisplatinum chemotherapy in murine breast cancer cells and a related in vivo model. MNPH was compared to conventional microwave tumor heating, with results suggesting that mNPH (mNP directly injected into the tumor and immediately activated) and 915 MHz microwave hyperthermia, at the same thermal dose, result in similar tumor regrowth delay kinetics. However, mNPH shows significantly less peri-tumor normal tissue damage. MNPH combined with cisplatinum also demonstrated significant improvements in regrowth delay over either modality applied as a monotherapy. Additional studies demonstrated that a relatively short tumor incubation time prior to AMF exposure (less than 10 minutes) as compared to a 4-hour incubation time, resulted in faster heating rates, but similar regrowth delays when treated to the same thermal dose. The reduction of heating rate correlated well with the observed reduction in mNP concentration in the tumor observed with 4 hour incubation. The ability to effectively deliver cytotoxic mNPs to metastatic tumors is the hope and goal of systemic mNP therapy. However, delivering relevant levels of mNP is proving to be a formidable challenge. To address this issue, I assessed the ability of cisplatinum to simultaneously treat a tumor and improve the uptake of systemically delivered mNPs. Following a cisplatinum pretreatment, systemic mNPs uptake was increased by 3.1 X, in implanted murine breast tumors. Additional in vitro studies showed the necessity of a specific mNP/ Fe architecture and spatial relation for heat-based cytotoxicity in cultured cells.
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Burrow, Shuna M. "The membrane as a barrier or target in cancer chemotherapy." Thesis, University of Central Lancashire, 1997. http://clok.uclan.ac.uk/7909/.
Full textAbstract:
The overall aim of the project was to investigate the role of the cell membrane as a barrier and/or target for drug action and relate this to the development of strategies for overcoming multiple drug resistance (MDR). The effects of doxorubicin on various bacterial strains expressing different levels of anionic phospholipid were compared. Giowth of wild-type Echerichia coli (E. coli) strain MRE600 was severely affected up to 9 hours following doxorubicin treatment (15uM), but resistance occurred after 9 hours. E. coli strain FIDL1 1 was resistant to doxorubicin (1 O0piM) over 9 hours, however, increasing the anionic lipid content showed little difference in sensitivity. The mouse mammary tumour cell line (EMT6-S) and MDR sub-line (EMT6-R) were characterised with regard to growth kinetics, susceptibility to doxorubicin and membrane lipid composition. The log phase doubling times (h) were found to be 21.8 (EMT6-S)and 25.0 (EMT6-R) and the IC 50 values for doxorubicin to be 2.2 x 10-8 M and 1.8 x 10-6 M for EMT6-S and EMT6-R cells, respectively. No difference was observed between the phospholipid profiles of the two cell lines and total fatty acid composition was similar, however, the level of linoleic acid appeared to be higher in the resistant cells. The photocytotoxicity of the cationic dyes methylene blue (MB), toluidine blue (TBO) and Victoria blue BO (VBBO) against the EMT6 cell lines was compared to the cyotoxic effect of doxorubicin and cis-platinurn. The cytotoxic effect of VBBO was enhanced 10-fold by illumination (7.2 J cm2) in both EMT6-S and EMT6-R cells. In order to overcome resistance, however, the EMT6-R cells required a 10-fold greater level of the dye than the parental cells to reach an IC50 value. By contrast, doxorubicin required almost a 100-fold increase in concentration to overcome this resistance. Pre-treatment of EMT6-S and EMT6-R cells with low concentrations of VBBO resulted in a 2-fold increase in doxorubicin toxicity in both cell lines. Pre-treatment with MB and TBO resulted in a 1.4-fold and 2-fold increase in doxorubicin toxicity, respectively, in the sensitive cells, increasing to 2-fold and 3-fold, respectively in the resistant cells. Glutathione (GSH) depletion of EMT6-S and EMT6-R cells did not enhance the photocytotoxicity of VBBO, suggesting that the primary site of action of VBBO is at an intracellular site not protected by GSH or that the mechanism of action is not via the in situ generation of singlet oxygen. Addition of the chemosensitizer, verapamil (7gM), increased the efficacy of doxorubicin by 2-fold in EMT6-S cells and by 18-fold in EMT6-R cells. By contrast, the presence of verapamil did not increase the cytotoxicity of YBBO in either cell line. A series of compounds, PVB, MVB and MOVB, based on the skeleton of VBBO was examined. VBBO was found to be the most effective photosensitizer. The rate of uptake for VBBO, MVB and PVB appeared to be very similar, whereas that of MOVB was slower. The uptake/dose trend was also similar four all four drugs tested and conelated to the levels of lipophilicity of the agents. Confocal microscopy studies showed all the photosensitizers to be distributed widely throughout the cytoplasm, with considerable accumulation of VBBO and PVB in the perinuclear region. Time course studies showed the intracellular distribution of VBBO in both cell lines to be similar, although uptake of the drug appeared slower in the resistant cell line. VBBO was clearly localised throughout the cytoplasm, in a punctate pattern, which may be consistent with the widespread distribution of mitochondria. No interaction with the plasma membrane was evident. By contrast, doxorubicin was found to localise mainly in the nucleus of the sensitive cell line, whereas no nuclear involvement was seen in the resistant cells. The drug was also effluxed more rapidly from EMT6-R cells than EMT6-S cells. Time course studies with EMT6-S cells showed that the drug clearly interacts with both the plasma membrane and the nucleus. These results indicate that the main modes of action for the two drugs differ markedly, suggesting interaction with both the membrane and the nucleus in the case of doxorubicin, but possibly mitochondrial involvement for VBBO.
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Beech, Adam. "Metabolic profiling analysis of pharmacodynamic responses to chemotherapy in cancer." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/51548.
Full textAbstract:
Cancer is one of the leading causes of death worldwide, and various chemotherapeutic agents are in use for its treatment. However, response to these therapies is generally low and resistance to these drugs is a daunting problem for cancer intervention. Prediction of response to drug treatment and the pharmacodynamics of response following treatment are important avenues for research into the clinical efficacy of chemical interventions in cancer, and in the goal of personalisation of medicine through patient stratification. This research project investigated potential pharmacodynamic biomarkers of response to anticancer drugs through metabonomics, assessing molecular changes in metabolic profile following specific drug treatments. Ultra-performance liquid chromatography-mass spectrometry was used in an untargeted approach on in vitro and in vivo sample sets. Multivariate modelling and statistics were employed alongside database interrogation to identify potential metabonomic biomarkers of response to treatment in three studies: in vitro treatment of breast cancer cells with histone methyltransferase inhibitors; in vitro and in vivo investigation of epidermal growth factor receptor inhibition in colorectal cancer; and in vivo assessment of platinum resensitisation using AKT inhibition in ovarian cancer. Across the three studies compositional changes in the abundance of several lipids based on treatment was seen, with several phosphatidylcholines, sphingomyelins and ceramides consistently found to increase in concentration in cells or patients that responded to therapy. Polar metabolites that were found to change in level as a result of treatment were more specific to each study. Each tentative identification represents a potential biomarker of treatment response, and requires ID confirmation with chemical standards and fragmentation before further investigating further. The trajectory of the results points to the feasibility of metabonomic biomarkers in early clinical trials as pharmacodynamic and response biomarkers that have the potential to optimise therapy for each cancer patient.
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Robinson, Timothy. "Targeting cFLIP to inhibit residual cancer stem cells after chemotherapy." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/107539/.
Full textAbstract:
The emergence of the cancer stem cell (CSC) hypothesis has helped to explain previously poorly understood clinical concepts such as metastases, late tumour recurrence and resistance to chemotherapy. Triple Negative Breast Cancer (TNBC) has the worst prognosis of all types of breast cancer with a more frequent relapse rate and reduced length of survival in metastatic disease. It has been shown to contain a higher proportion of CSCs than other types of breast cancer. Paclitaxel, a taxane in widespread use in breast cancer, induces apoptosis in a ligand-independent manner through the extrinsic apoptosis pathway. cFLIP is both an antagonist of this apoptosis pathway and can interfere with the ubiquitynation and subsequent degradation of both HIF1α and β-catenin, two molecules involved in CSC-signalling. Using a novel compound targeted against cFLIP, we wanted to assess whether its combination with paclitaxel effectively targeted CSCs. Using a combination of in vitro models of cancer stem/progenitor-like activity and the surrogate marker of CSCs, ALDH, we demonstrated that a number of chemotherapeutic agents, including paclitaxel, docetaxel and FEC increased CSC-like behaviour. A mathematical model demonstrated that paclitaxel increased the absolute number of CSCs after treatment suggesting that CSC-like activity was being induced. OH14, a novel inhibitor of c-FLIP developed in our laboratory, abrogated the paclitaxel-mediated induction of CSC-like activity in TNBC cell lines. While apoptosis may play a role in CSC viability in vitro, it did not appear to play a major role in OH14-mediated suppression of CSC acquisition following paclitaxel treatment. Instead, OH14 appeared to suppress CSCs through disruption of HIF1- α, as HIF1α-mediated signalling was increased by paclitaxel and abrogated by the addition of OH14. These beneficial effects of combinatorial OH14 were confirmed in vivo, where OH14 suppressed tumour initiation of TNBC xenografts and prevented relapse of paclitaxel treated tumours in a xenograft model of systemic treatment. cFLIP thus has a dual effect in both increasing apoptosis and targeting signalling in TNBC CSCs. In a breast cancer subtype in desperate need of novel therapeutic strategies, targeting cFLIP warrants further investigation and progression towards clinical trials.