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1
Tong, Zhimin. "The mechanisms of cellular sensitivity to photodynamic therapy /." *McMaster only, 2001.
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2
Landry, Benjamin D. "Tumor-stroma interactions differentially alter drug sensitivity based on the origin of stromal cells." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/1011.
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Tumor heterogeneity observed between patients has made it challenging to develop universal or broadly effective cancer therapies. Therefore, an ever-growing movement within cancer research aims to tailor cancer therapies to individual patients or specific tumor subtypes. Tumor stratification is generally dictated by the genomic mutation status of the tumor cells themselves. Importantly, non-genetic influences – such as interactions between tumor cells and other components of the tumor microenvironment – have largely been ignored. Therefore, in an effort to increase treatment predictability and efficacy, we investigated how tumor-stroma interactions contribute to drug sensitivity and drug resistance.
I designed a high throughput co-culture screening platform to measure how tumor-stroma interactions alter drug mediated cell death. I identified tumor-stroma interactions that strongly desensitize or sensitize cancer cells to various drug treatments. The directionality of these observed phenotypes was dependent on the stromal cell tissue of origin. Further study revealed that interactions between tumor cells and fibroblasts modulate apoptotic priming in tumor cells to mediate sensitivity to chemotherapeutics. The principles uncovered in this study have important implications on the use of drugs that are designed to enhance apoptosis. For example, based on our screening data, I hypothesized and experimentally validated that the effectiveness of BH3 mimetic compounds would be strongly dependent on the fibroblast growth environment. Taken together, our study highlights the importance of understanding how environmental interactions alter the drug responses of cancer cells and reveals a mechanism by which stromal cells drive broad spectrum changes in tumor cell sensitivities to common chemotherapeutics.
3
Ferguson, Paul R. "The role of thymidylate synthase in modulating sensitivity to chemotherapeutic agents." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326399.
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4
Fung, Ka-lai. "Significance of MAD2 in mitotic checkpoint control and cisplatin sensitivity of testicular germ cell tumour cells." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38588912.
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5
Kanwal, Shahzina. "Effect of O-GlcNAcylation on tamoxifen sensitivity in breast cancer derived MCF-7 cells." Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-00912341.
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One of the hallmarks of cancer cells is to exhibit increased uptake and consumption of glucose.3-5% of the glucose entering into the cell leads to a minor pathway of the glucose metabolismknown as the hexosamine biosynthetic pathway (HBP). UDP-N-acetylglucosamine is the endproduct of HBP and is used as substrate by OGT (O-GlcNAc transferase) to modify diverserange of nuclear and cytoplasmic proteins with a recently characterized post-translationalmodification called O-GlcNAcylation. It corresponds to the addition of sugar moiety O-linked β-N-acetylglucosamine (O-GlcNAc) on serine or threonine residue of proteins. This process isantagonized by another enzyme called O-GlcNAcase (OGA). Recent studies indicated thepresence of increased O-GlcNAcylation level in several cancer cells. Moreover, inhibition ofOGT has been shown to reduce in vivo and in vitro tumor growth of breast cancer cells.However, the relationship between O-GlcNAcylation and the response to anti-cancer therapy hasnot been studied. Tamoxifen is the oldest and most prescribed selective-estrogen receptormodulator (SERM) for patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen isknown to reduce tumor growth and invasion. Despite its beneficial effects de novo and acquiredresistance are great obstacles in its clinical effectiveness. We found that O-GlcNAc elevation inMCF-7 cells protected them from tamoxifen-induced cell death. Increased O-GlcNAc alsoincreased PI3-K/Akt signaling. However, the protective effect of PUGNAc+glucosamine fromtamoxifen-induced cell death is independent of PI3K/Akt pathway. Increased O-GlcNAcylationalso led to reduced ESR1 promoter activity and decreased expression of ERα at mRNA andprotein levels. The decrease in ERα expression is correlated with a reduced expression of twotamoxifen regulated genes i.e. early growth response 1 and p21 Waf1/Cip1. In conclusion, thisstudy showed for the first time the involvement of O-GlcNAcylation in reducing tamoxifen142sensitivity in MCF-7 cells. Thus, OGT can act as a novel therapeutic target for treatment oftamoxifen resistant cells.
6
Sureechatchaiyan, Paichat [Verfasser]. "Role of Purinergic Ligands to Enhance Cisplatin Sensitivity in Ovarian Cancer Cells / Paichat Sureechatchaiyan." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2017. http://d-nb.info/1148066756/34.
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7
Fung, Ka-lai, and 馮家禮. "Significance of MAD2 in mitotic checkpoint control and cisplatin sensitivity of testicular germ cell tumour cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39357727.
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8
Zhang, Pingde, та 张萍德. "TAp73α enhances the cellular sensitivity to cisplatin in ovarian cancer cells via the JNK signaling pathway". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47752944.
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Ovarian cancer is the most lethal gynecological malignancy. Most of ovarian
cancer patients relapse and subsequently die due to the development of resistance
to chemotherapy. P73 belongs to the tumor suppressor p53 family. Like p53, the
transcriptionally active TAp73 can bind specifically to p53 responsive elements
and transactivates some of the p53 target genes, and finally leads to cell cycle
arrest and apoptosis. TAp73 can be induced by DNA damage to enhance cellular
sensitivity to anticancer agents in human cancer cells. However, the functions of
TAp73 in ovarian cancer cells and the role in the regulation of cellular response to
commonly used chemotherapeutic agents cisplatin are still poorly understood. The
aims of this study were to examine the functions of TAp73 in ovarian cancer cells
and its role in cellular response to cisplatin, as well as the relationship between
TAp73 and p53 in ovarian cancer cells.
Functional studies showed that over-expression of TAp73alpha (TAp73α)
inhibited cell proliferation, colony formation ability and anchorage-independent
growth of ovarian cancer cells, and this was irrespective of p53 expression status.
In addition, TAp73α inhibited cell growth by arresting cell cycle at G2/M phase
and up-regulating the expressions of G2/M regulators of p21, 14-3-3sigma and
GADD45α.
TAp73α enhanced the cellular sensitivity to cisplatin through the activation of
JNK signaling pathway, at least partially, in ovarian cancer cells. TAp73α
activated the JNK pathway through the up-regulation of its target gene GADD45α
and subsequent activation of MKK4, the JNK up-stream kinase. Inhibition of JNK
activity by a specific inhibitor (SP600125) or small interfering RNAs (siRNAs)
significantly abrogated TAp73-mediated apoptosis induced by cisplatin. Moreover,
the activations of MKK4, JNK and c-Jun were abolished when GADD45α was
knocked down by siRNAs, and the JNK-dependent apoptosis was not observed.
Collectively, these results supported that TAp73α was able to mediate apoptotic
response to cisplatin through the GADD45α/MKK4/JNK signaling pathway,
which was respective of p53 expression status.
Further investigation on the relationship between TAp73α and p53
demonstrated that TAp73α increased p53 protein, but not mRNA expression by
attenuating p53 protein degradation in wild-type p53 ovarian cancer cells.
TAp73α could directly interact with p53 protein, which might interfere with the
binding ability of MDM2 to p53, and consequently block the p53 protein
degradation. In addition, TAp73α inactivated the Akt and ERK pathways and
activated the p38 pathway in response to cisplatin in wild-type p53 OVCA433,
but not in null-p53 SKOV3 cells, suggesting that the effect of TAp73α on these
pathways might be p53-dependent. These results indicated that a functional
cooperation of TAp73α and p53, to some extent, existed in ovarian cancer cells.
In conclusion, this study demonstrated that TAp73α acted as a tumor
suppressor in ovarian carcinogenesis. It promoted the cellular sensitivity to
cisplatin via, at least partially, the activation of JNK signaling pathway. These
TAp73α functions were irrespective of p53 expression. In addition, TAp73α was
able to bind to p53 and increase p53 expression.<br>published_or_final_version<br>Obstetrics and Gynaecology<br>Doctoral<br>Doctor of Philosophy
9
Newbury, Golnar. "A Numerical Study of a Delay Differential Equation Model for Breast Cancer." Thesis, Virginia Tech, 2007. http://hdl.handle.net/10919/34420.
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In this thesis we construct a new model of the immune response to the growth of breast cancer cells and investigate the impact of certain drug therapies on the cancer. We use delay differential equations to model the interaction of breast cancer cells with the immune system. The new model is constructed by combining two previous models. The first model accounts for different cell cycles and includes terms to evaluate drug treatments, but ignores quiescent tumor cells. The second model includes quiescent cells, but ignores the immune response and drug treatments. The new model is obtained by combining and modifying these two models to account for quiescent cells, immune cells and includes drug intervention terms. This new model is used to evaluate the effects of pulsed applications of the drug Paclitaxel for models with and without quiescent cells. We use sensitivity equation methods to analyze the sensitivity of the model with respect to the initial number of immune cytotoxic T-cells. Numerical experiments are conducted to compare the model predictions to observed behavior.<br>Master of Science
10
Dilruba, Shahana [Verfasser]. "Impact of ERK signaling and its spatial regulation on cisplatin sensitivity in ovarian cancer cells / Shahana Dilruba." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1220912638/34.
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11
Jokinen, E. (Elina). "Targeted therapy sensitivity and resistance in solid malignancies." Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526205755.
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Abstract Cancer is a major global killer and a challenge for the healthcare worldwide. Earlier cancer has been treated with surgery, radiation, chemotherapy and hormonal therapy. Unfortunately the efficiency of these therapies has shown to be limited and this has raised an enthusiasm for development of new, targeted cancer therapies that are based on activated oncogenes. The challenge of the targeted therapies is therapy resistance, de novo, adaptive and acquired. This work investigated targeted therapy sensitivity and resistance in lung cancer, breast cancer, colorectal cancer, and melanoma cell lines. The results of this study indicate that in some non-small cell lung cancer cell lines, dual PI3K and MEK inhibition is a more efficacious treatment than inhibition of either solely. It was also showed that the maximal effect of the dual inhibition can be achieved with alternative dosing schedules that are potentially more tolerable in clinical use. Furthermore, by combining ABT-263, entinostat or dasatinib to the dual PI3K and MEK inhibition, the efficiency of the therapy can be increased. Bcl-xl downregulation is a major determinant of the apoptotic response to the triple inhibitor treatment. The current work showed that cancer stem cells can mediate resistance to targeted therapies. Since these cells follow the stochastic model, concurrent therapy with a targeted agent and a stem cell targeting drug might be needed for maximal therapeutic efficiency. This study also showed that Gö6976 acts as a potent inhibitor of mutant EGFR despite the presence of T790M, the most important mechanism of acquired resistance for EGFR tyrosine kinase inhibitors in lung cancer, both in vitro and in vivo<br>Tiivistelmä Syöpä on yksi johtavia kuolemanaiheuttajia ja tauti on maailmanlaajuinen haaste terveydenhuollolle. Perinteiset syöpähoidot käsittävät kirurgian, sädehoidon, kemoterapian ja hormonaalisen hoidon, mutta näiden rinnalle on noussut uusia, aktivoituneiden onkogeenien signaalien estoon perustuvia hoitoja. Tämä työ tutki kohdennettuja syöpähoitoja ja näihin hoitoihin liittyvää resistenssiä keuhko-, rinta- ja paksusuolen syövän sekä melanooman solulinjoissa. Tulokset osoittavat, että joissakin ei-pienisoluisen keuhkosyövän solulinjoissa yhdistetty PI3K- ja MEK-esto aiheuttaa tehokkaamman vasteen kuin kummankaan signaalireitin esto yksistään. Tässä työssä näytettiin myös, että maksimaalinen vaste yhdistetylle PI3K- ja MEK-estolle voidaan saavuttaa vaihtoehtoisilla annostelutavoilla, jotka ovat voisivat olla paremmin siedettyjä kliinisessä käytössä kuin kahden lääkkeen jatkuva annostelu. Tämä tutkimus osoitti lisäksi, että kaksoiseston tehokkuutta voidaan lisätä yhdistämällä hoitoon kolmas lääkeaine, ABT-263, entinostaatti tai dasatinibi. Bcl-xl proteiinilla on keskeinen rooli apoptoottisen vasteen määrittäjänä näille kolmen lääkkeen käsittelyille. Tämä työ osoitti, että syövän kantasolut voivat välittää resistenssiä kohdennetuille syöpähoidoille. Nämä solut noudattavat niin kutsuttua stokastista mallia, joten parhaan vasteen saaminen saattaa edellyttää että hoito kohdentuu sekä erilaistuneisiin että kantasolutyyppisiin syöpäsoluihin. Tässä tutkimuksessa osoitettin lisäksi, että Gö6976 toimii mutatoituneen EGFR:n estäjänä, huolimatta kehittyvää keuhkosyövissä resistenssiä välittävästä T90M mutaatiosta, sekä in vitro -että in vivo -malleissa
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Chan, Dana C. "THE EFFECT OF SILENCING THE WILMS' TUMOR 1 GENE ON THE RADIATION SENSITIVITY OF GLIOBLASTOMA CELLS." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/1483.
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13
Meacham, Amy Marie. "Relationship of dna methyltransferases, dnmt3a and dnmt3b, and 5-aza-2'-deoxycytidine sensitivity among various cancer cell lines." [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0010443.
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Thesis (M.S.)--University of Florida, 2005.<br>Typescript. Title from title page of source document. Document formatted into pages; contains 50 pages. Includes Vita. Includes bibliographical references.
14
Ladha, Shabirali. "The effect of changes in plasma membrane lipid composition on the heat sensitivity of hepatoma tissue culture cells and selected plasma membrane enzymes." Thesis, Durham University, 1990. http://etheses.dur.ac.uk/6197/.
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Hepatoma Tissue Culture (HTC) cells grown in the presence of 60µM arachidonic acid for 24, 36 and 48 hours became progressively more thermosensitive than control cells. However, this difference in thermal sensitivity was only detectable with the clonogenic assay and not with the colorimetric assay. Attempts were also made to manipulate cellular cholesterol levels. Firstly, some cells were incubated with phosphatidylcholine liposomes to deplete the plasma membrane of cholesterol: Secondly, another group of cells were treated with 25 hydroxycholesterol, an inhibitor of cholesterol synthesis, to lower cholesterol levels: Finally, a third group of cells were supplemented with cholesterol hemisuccinate, a hydrophilic ester of cholesterol. The first two approaches did not enhance the thermal sensitivity of HTC cells. Supplementation with cholesterol hemisuccinate, which was predicted to partition in to the plasma membrane and reduce membrane fluidity, resulted in increased thermal sensitivity of the cells. Thus, the thermal sensitivity of HTC cells could be enhanced by supplementation with either arachidonate or cholesterol hemisuccinate. A rapid plasma membrane isolation procedure was developed which generated plasma membranes in relatively high yield and purity. The plasma membrane- enriched fraction was also assayed for contaminating intracellular membranes by determining marker enzyme activities associated with these membranes. Using this method, plasma membranes were prepared from HTC cells grown m 60µM arachidonic acid for 36 hours and from cells grown in normal medium. Analysis of the plasma membrane showed that the arachidonic acid content of the phospholipid fatty acyl groups had been significantly increased in cells grown in the presence of this fatty acid. There was no change in the cholesterol/phospholipid molar ratio or cholesterol concentration relative to amount of protein in the plasma membranes from the two cell populations. The measurement of fluidity using DPH fluorescence polarisation revealed that the increase in the arachidomc acid content of the plasma membrane phospholipid acyl groups was associated with enhanced plasma membrane fluidity when compared to control plasma membranes. This increase in plasma membrane fluidity correlated with the enhanced thermal sensitivity of the cells grown in arachidonic acid-containing medium when compared to cells grown in normal medium. Furthermore, the thermal sensitivity of Na(^+), K(^+) –ATPase and alkaline phosphodiesterase I were assessed in plasma membranes derived from arachidonic acid-supplemented and control cells. The enhanced fluidity of plasma membranes derived from arachidonate-supplemented cells also correlated with increased thermosensitivity of alkaline phosphodiesterase I.
15
Hauser, Jennifer E. M. S. "Genetic Epidemiology of Radiation Sensitivity and Basal Cell Carcinoma in Childhood Cancer Survivors." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689192.
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16
Lymperatou, Dionysia. "Exploring the impact of anti-oestrogen resistance on the capacity of breast cancer cells to modulate bone cell function and their sensitivity to bisphosphonates." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/109360/.
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Acquired resistance to endocrine therapy is a major limiting factor for their clinical effectiveness, resulting in disease relapse and an associated poor prognosis. Acquired resistance is also associated with the development of an invasive and migratory phenotype in vitro that may promote metastatic spread in vivo of which bone is the most frequent site. However, it is not currently known whether endocrine resistance affects the ability of breast cancer cells to modulate bone cell function important in establishing bone metastases or whether a resistant phenotype alters sensitivity to agents commonly used to treat bone metastasis such as bisphosphonates. Thus, this thesis aimed to explore the bone cell modulatory function of endocrine resistant and sensitive breast cancer cells along with their sensitivity to the bisphosphonate, zoledronic acid. This thesis demonstrated that breast cancer cells were able to directly induce osteoclast differentiation from both murine and human precursor cells. Importantly, this effect was more prevalent in tamoxifen resistant and triple negative breast cancer subtypes. Our data also suggested that the breast cancer-mediated osteoclastogenic effect involved Src kinase, whilst bisphosphonates acted as anti-tumour agents in tamoxifen resistant cells through inhibition of EGFR/AKT/mTOR pathway. In conclusion, this thesis suggests that acquisition of endocrine resistance confers a bone modulatory ability to breast cancer cells that may contribute to the development of bone metastases. However, this thesis reports the novel finding that acquired endocrine resistance augments the sensitivity of breast cancer cells to bisphosphonates, thus representing an opportunity to target resistant disease clinically.
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Huichalaf, Carbonell Mariela [Verfasser], and Stefan [Akademischer Betreuer] Wölfl. "Metabolic Profiling of Cancer Cells and Correlations between Metabolism, Gene Expression and Drug Sensitivity / Mariela Huichalaf Carbonell ; Betreuer: Stefan Wölfl." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177383950/34.
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18
Guo, Yang. "Overexpression of Heat-Shock Protein 27 (HSP27) increases gemcitabine sensitivity in pancreatic cancer cells through s-phase arrest and apoptosis." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-176979.
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19
Valiathan, Chandni Rajan. "Identifying a transcriptional signature for cell sensitivity to the cancer chemotherapy agent, BCNU." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/65773.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Computational and Systems Biology Program, 2011.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references.<br>Many organisms have evolved DNA damage response mechanisms to deal with the constant damage to DNA caused by endogenous and exogenous agents. These mechanisms activate cell cycle checkpoints to allow time for DNA repair or, in the case of severely damaged DNA, initiate cell death mechanisms to maintain genomic integrity. The cell's response to DNA damaging agents includes wide spread changes in the transcriptional state of the cell that have been implicated in cell death or survival decisions. However, we do not fully understand how the multiple and sometimes opposing transcriptional signals are interpreted to make these critical decisions. A computational and systems biology approach was taken to study the wide-spread transcriptional changes induced in human cell lines after exposure to a DNA damaging and chemotherapeutic agent, 1,3-bis-(2-chloroethyl)- 1 -nitrosourea (BCNU or carmustine). Cell lines with extreme sensitivity or resistance to BCNU were identified from a set of twenty four genetically diverse human lymphoblastoid cell lines using a high-throughput method that was developed as part of this thesis. This assay has broad applications and can be used to simultaneously screen multiple cell lines and drugs for accurate measurements of cell proliferation and survival after drug treatment. The assay has the advantage of having a large dynamic range that allows sensitivity measurements on a multi-log scale allowing better resolution of comparative sensitivities. Temporal transcription profiles were measured in cell lines with extreme BCNU sensitivity or resistance to generate a large transcription data set amenable to bioinformatics analysis. A transcriptional signature of 706 genes, differentially expressed between BCNU sensitive and resistant cell lines, was identified. Network and gene ontology enrichment identified these differentially expressed genes as being involved in key DNA damage response processes like apoptosis and mitosis. Experimental evidence showed that the transcription signature correlated with observed cellular phenotypes. Furthermore, the NF-Y transcription factor binding motif was enriched in the promoter region of 62 mitosis-related genes downregulated in BCNU sensitive but not resistant cell lines. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) confirmed NF-Y occupancy in 54 of the 62 genes, thus implicating NF-Y as a possible regulator of the observed stalling of entry into mitosis. Using experimental and computational techniques we deciphered the functional importance of differential transcription between BCNU sensitive and resistant cell lines and identified NF-Y as an important factor in the transcriptional and phenotypic cell response to BCNU such as the control of entry into mitosis.<br>by Chandni Rajan Valiathan.<br>Ph.D.
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Oatman, Nicole. "Mechanisms regulating cancer cell sensitivity and acquired resistance to Stearoyl-CoA Desaturase inhibition." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573572568302598.
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21
Kozlak, Maria. "AsiDNA, a Unique DNA Repair Inhibitor, Triggers Sensitization and Bioenergetic Adaptation in Cancer Cells." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS101.
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Le but d’un traitement anticancéreux est d’être spécifique et efficacité dans la durée vis-à-vis des cellules tumorales. De nombreux agents chimiothérapeutiques ont rencontré des obstacles quant à leur utilisation en raison de leur toxicité pour les cellules saines ou de la résistance développée par les cellules cancéreuses. Cela souligne la nécessité de développer des médicaments alternatifs. Notre laboratoire a développé une classe d'inhibiteurs de réparation de l'ADN, Dbait, qui agissent en détournant et en hyperactivant les protéines de la réparation de l’ADN, telles que la protéine PARP et DNA-PK. Cela conduit en conséquence à des modifications de la chromatine, visualisées par la phosphorylation pan-nucléaire de l’histone H2AX, et en l’inhibition du recrutement aux sites des dommages de plusieurs protéines de réparation. AsiDNA, une forme active de Dbait, sensibilise les tumeurs aux radiations, à la chimiothérapie, à la thérapie ciblée, sans effet sur les cellules non tumorales et les tissus sains. Dans la mesure où la chimiothérapie consiste en des traitements cycliques de l'agent anti-cancéreux, l'objectif de cette étude était d'étudier in vitro les conséquences d’un traitement répété d’AsiDNA sur les cellules tumorales et non tumorales, plus particulièrement pour ce qui concerne l’émergence de clones tumoraux résistants ou inversement de clones non tumoraux devenus sensibles au traitement. Dans un premier temps, nous avons conçu des expériences dans le but d'isoler des clones résistants au traitement par AsiDNA. Nous montrons que des traitements cycliques ne conduisent pas à des clones résistants, mais au contraire à la sélection de cellules tumorales caractérisées par une hyper sensibilité à l'AsiDNA. Cette sensibilité acquise est stable dans le temps et n'a jamais été observée en traitant des cellules non tumorales. Afin d’identifier le(s) mécanisme(s) responsable(s) de cette sensibilité acquise, nous avons comparé des cellules de sein non tumorales (MCF-10A) et tumorales triples négatives (MDA-MB-231) après 3 trois cycles de traitement par AsiDNA. Nous montrons que les traitements cycliques d'AsiDNA causent une inhibition de l'expression génique, essentiellement au niveau de gènes impliqués dans la réparation de l'ADN, le cycle cellulaire et la prolifération. Néanmoins, aucune différence dans la capacité de réparation de l'ADN, la progression du cycle cellulaire et le taux de prolifération n'est observable. Les cellules cancéreuses augmentent les voies métaboliques énergétiques pour produire d’énergie nécessaire à leur prolifération. En tenant compte du fait que l’expression de certains gènes impliqués dans les voies métaboliques sont aussi dérégulées par le traitement cyclique d’AsiDNA, nous avons émis l’hypothèse que l’épuisement métabolique pouvait être responsable de la sensibilisation des cellules tumorales à l’AsiDNA. Une étude du métabolome a révélé une dérégulation de plusieurs métabolites incluant NAD+. Nous montrons que cette dérégulation bioénergétique est responsable de l'hypersensibilité acquise des cellules cancéreuses suite au traitement par AsiDNA. Une étude bioénergétique des cellules tumorales non traitées et sélectionnées après les traitements cycliques par AsiDNA confirment une diminution de glycolyse aérobique et de la phosphorylation oxydative dans ces dernières. En conséquence de cette réduction énergétique, les cellules cancéreuses ont perdu leur caractère malin, ce qui est démontré par une inhibition de la migration et de la formation de tumeur. Nous montrons que les cellules tumorales dérivées de traitements cycliques par AsiDNA sont dépourvues de cellules souches cancéreuses dont les caractéristiques sont leur résistance aux drogues et leur phénotype invasif. En conclusion, à côté de son rôle dans l'inhibition de la réparation de l'ADN, AsiDNA interfère également avec le métabolisme énergétique des cellules cancéreuses<br>The goal of anti-cancer treatment is long term specificity and efficacy towards cancer cells. Many of the clinically available chemotherapy have encountered obstacles due to their toxicity towards healthy cells or to development of resistance by the cancer cells. This emphasizes the need for development of alternative drugs. Our laboratory developed an original class of DNA repair inhibitor, Dbait, that acts by hijacking and hyper activating DNA repair proteins involved in repairing DNA breaks, such as PARP and DNA-PK. Consequently, this leads to chromatin modification, as revealed by pan-nuclear phosphorylation of H2AX, and inhibition of the recruitment at the damage site of several DNA repair proteins at the damage site. AsiDNA, an active form of Dbait linked to a cholesterol moiety, sensitizes tumours, and not non-tumour cells, to radiation, chemotherapy, targeted therapy. As most of clinical protocols of chemotherapy involve cyclic treatments, the aim of this study was to investigate consequences of cyclic AsiDNA treatment in vitro on non-tumor and tumor cells, conditions that experience cancer patients during chemotherapy. Particular emphasis was paid to emergence of resistant clones during cyclic AsiDNA treatment of tumour cells and emergence of toxicity toward normal cells. At first, various tumor and non-tumor cells were exposed to cyclic treatments consisting of one week of treatment and one week of drug-free recovery. After few cycles of treatment, we didn’t observe toxicity toward normal cells and we failed to isolate resistant clones to AsiDNA from tumor cells. Importantly, this treatment protocol induced resistance of MDA-MB-231 cells to imatinib or PARPi. Unexpectedly, we observed that sensitivity to AsiDNA increased with repeated cycles in tumor cells. This acquired sensitization was stable over time and was never observed in non-tumor cells. In an attempt to understand the specific and acquired sensitization of tumor cells along treatment, we compared non-tumor (MCF-10A) and triple-negative breast cancer (MDA-MB-231) cells that were exposed (3CAsiDNA) or not (3CMT) to 3 rounds of AsiDNA. Transcriptome analysis of MDA-MB-231 revealed global downregulation of transcription after cyclic AsiDNA treatment. Although the expression of genes involved in DNA repair, cell cycle and proliferation, was highly affected, strikingly no clear difference in DNA repair capacity, cell cycle or proliferation rate was observed between MDA-MB-231_3CAsiDNA and MDA-MB-231_3CMT. In contrary, modification of gene expression was weakly affected in non-tumor cells.As impaired DNA repair capacity or cell cycle deregulation couldn’t explain this acquired sensitivity, therefore alternative mechanisms should account for the higher mortality of cyclic treated AsiDNA cells. Cancer cells upregulate energy metabolic pathways to produce enough energy for cell proliferation and repair. Noteworthy, AsiDNA is a PARP activator requiring NAD+ consumption. Based on the fact that metabolic pathways were also deregulated at the transcriptional level, we hypothesized that metabolic exhaustion may be responsible for AsiDNA induced sensitization. Metabolome study revealed deregulation of several metabolites including NAD+. We showed that this bioenergetics deregulation is responsible for increasing sensitivity to AsiDNA. Bioenergetics study confirmed low metabolic activity after repeated AsiDNA treatment due to deregulating aerobic glycolysis and oxidative phosphorylation. As a consequence of energetic deprivation, cancer cells deregulated their malignant behavior by inhibition of migration and tumor formation. We showed that 3CAsiDNA tumor cells are depleted of cancer stem cells, which features are responsible of drug resistance and cancer invasive phenotype. Altogether, we demonstrated that AsiDNA, beside its role in DNA repair inhibition, also interferes with energy metabolism in cancer cells
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Siu, Wing-fai, and 邵穎暉. "Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor and androgen sensitivity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B23829850.
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Siu, Wing-fai. "Melatonin and prostate cancer cell proliferation : interplay with castration, epidermal growth factor and androgen sensitivity /." Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23829850.
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Law, Edward William Preston. "Determining mechanisms of sensitivity and resistance to HSP90 inhibition in non-small cell lung cancer." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/38121.
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BACKGROUND: HSP90 is a molecular chaperone which supports the maturation of numerous client proteins, many of which are involved in oncogenic signaling pathways such as PI3K/AKT, MAPK and JAK/STAT. HSP90 is an appealing target for small molecule inhibitors due to its ability to simultaneously downregulate multiple oncogenic conduits. Results in the clinic have been mixed and biomarkers of response to HSP90 inhibitors for patient stratification remain obscure. RESULTS: 1. EML4-ALK is a HSP90 client which degrades in response to HSP90 inhibition. Variants of EML4-ALK exist with disparate structures and stabilities. This chapter demonstrates differential stability of EML4-ALK variants and cell line sensitivity in response to HSP90 inhibition. A RT-PCR test to identify variants from FFPE tumour tissue is developed for tissues from the CHIARA trial to link variant status and response to ganetespib. 2. Characterisation of a cell line resistant to ganetespib, and verification that high UGT1A levels prevent ganetespib from inhibiting HSP90 in a NSCLC context. 3. Array-based analysis of genome-wide copy number alterations in the GALAXY-1 trial, which examined ganetespib plus docetaxel (G-D) in the second line setting against docetaxel alone (D), following platinum-based chemotherapy in NSCLC patients. Three CNAs were associated with sensitivity to ganetespib plus docetaxel: loss in cytoband 18q23, and gains in 11q13.3 and 16q22.3. Patients with multiple CNAs may represent a group of patients who perform badly on docetaxel but respond much better with the addition of ganetespib. SUMMARY: Several putative biomarkers which are predictive of response to ganetespib are identified in this study. The relationship between EML4-ALK variant stability and ganetespib response may shed light on HSP90 client selection. Genome wide CNA analysis associated with randomized clinical trial survival data has identified putative biomarkers of efficacy to ganetespib plus docetaxel.
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Panzilius, Elena [Verfasser], and Magdalena [Akademischer Betreuer] Götz. "Dissection and identification of cellular contexts that determine sensitivity to ferroptosis in human mammary epithelial cells and breast cancer / Elena Panzilius ; Betreuer: Magdalena Götz." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/121603916X/34.
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Guo, Yang [Verfasser], and Max [Akademischer Betreuer] Schnurr. "Overexpression of Heat-Shock Protein 27 (HSP27) increases gemcitabine sensitivity in pancreatic cancer cells through s-phase arrest and apoptosis / Yang Guo. Betreuer: Max Schnurr." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1062877586/34.
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Powell, Chase David. "Role of Heat Shock Transcription Factor 1 in Ovarian Cancer Epithelial-Mesenchymal Transition and Drug Sensitivity." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/7079.
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The heat shock response (HSR) is a robust cellular reaction to mitigate protein damage from heat and other challenges to the proteome. This protective molecular program in humans is controlled by heat shock transcription factor 1 (HSF1). Activation of HSF1 leads to the induction of an array of cytoprotective genes, many of which code for chaperones. These chaperones, known as heat shock proteins (HSPs), are responsible for maintaining the functional integrity of the proteome. HSPs achieve this by promoting proper folding and assembly of nascent proteins, refolding denatured proteins, and processing for degradation proteins and aggregates which cannot be returned to a functional conformation. The powerful ability of the heat shock response to promote cell survival makes its master regulator, HSF1, an important point of research. To garner a better understanding of HSF1, we reviewed the role of the highly dynamic HSF1 protein structure and investigated how HSF1 affects cancer cell behavior and drug response.
Cancers can be characterized in part by abhorrent replication, self-sufficient growth signaling, invasion, and evasion of apoptosis. HSF1 has been found to promote proliferation, invasion, and drug resistance in several types of cancer; including lung and ovarian cancer. Ovarian cancer has elevated levels of HSF1, but the role of HSF1 in ovarian cancer behavior had not been previously examined. Researching the role of HSF1 in ovarian cancer is merited, because treatment outcomes are poor due to the high frequency of late stage detection and drug resistance. We hypothesized that HSF1 is important in the malignant growth and drug resistance of ovarian cancer.
We have created ovarian cancer cell lines with inducible knockdown of HSF1 to investigate how HSF1 contributes to the behavior of ovarian cancer. This allowed us to examine the behavior of cells in the absence HSF1. Both 2D and 3D spheroid tissue culture models were used to study how HSF1 contributes to the growth and invasion of ovarian cancer cells after treatment with the transforming growth factor β (TGFβ) cytokine. Additionally, we studied how HSF1 reduction modulates the response to multiple therapeutic drugs. Our research shows that HSF1 induces epithelial-mesenchymal transition (EMT) in a 3D growth model. Our work also demonstrates that reduction of HSF1 sensitizes ovarian cancer cells to multiple drugs.
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Hultman, Bo. "Clinical and Experimental Studies in Peritoneal Metastases from Gastric Cancer." Doctoral thesis, Uppsala universitet, Kolorektalkirurgi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-197776.
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Gastric cancer (GC) is one of leading causes of death in the world, and peritoneal metastases (PM) are a major site of recurrence. PM from GC implies a poor prognosis, with median overall survival (mOS) approximately 3 months and no survival at five years. The aims of this thesis were to explore the incidence and evaluate prognostic factors for mOS of PM from GC in a defined population; to investigate the outcome of a new multimodal treatment; to analyse the treatment costs, and to investigate differences in drug sensitivity between individual patient samples and between various tumours. The incidence of loco-regional advanced GC was 3.8 per 100,000 person-years. Synchronous loco-regional GC in combination with synchronous distant metastasis was a negative prognostic factor while chemotherapy and good performance status, and radiotherapy plus chemotherapy were positive prognostic factors . There were no significant differences in mOS for the group of patients included during the period 2000-2004 versus 2005-2009, and this lack of improvement in mOS during the past decade justifies new treatment approaches. In a Phase II study of patients treated with neoadjuvant systemic chemotherapy followed by cytoreductive surgery + hyperthermic intraperitoneal chemotherapy, mOS was 14.3 months and for patients with macroscopically radical surgery mOS was 19.1 months. The mean overall cost of the loco-regional treatment was $145,700 compared to $59,300 with systemic chemotherapy treatment. In an ex vivo chemo-sensitivity test, it was determined that GC samples were equivalent to colorectal cancer in chemo-sensitivity to standard drugs and targeted drugs, whereas ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the drugs, arguing for individualized drug selection. The incidence of loco-regional advanced GC was more common than previously reported and there were no improvements in mOS over the past decade. The mOS for patients with neoadjuvant systemic chemotherapy followed by macroscopically radical cytoreductive surgery + hyperthermic intraperitoneal chemotherapy was better than in recent reports on treatment with systemic chemotherapy. Treatment of advanced GC patients is costly irrespective of treatment modality. The GC samples varied considerably between individuals in terms of sensitivity to increasing concentrations of the drugs and were comparable to colorectal cancer in chemo-sensitivity.
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Dabare, Abeysinghe Arachchige Nandike Prashanth M. "Development of new monoclonal antibodies and colorimetric assays for improved detection of testicular germ cell tumours (TGCTs) and determining the relevance of over-expressed P53 in TGCT sensitivity to treatment." Thesis, Queen Mary, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312172.
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Terry, Samantha Y. A. "A role for topoisomerase II alpha in chromosome damage in human cell lines." Thesis, University of St Andrews, 2010. http://hdl.handle.net/10023/873.
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Human response to ionising radiation (IR) shows a wide variation. This is most clearly seen in the radiation-response of cells as measured by frequencies of chromosomal aberrations. Different frequencies of IR-induced aberrations can be conveniently observed in phytohaemagglutin-stimulated peripheral blood T-lymphocytes from both normal individuals and sporadic cancer cases, in either metaphase chromosomes or as micronuclei in the following cell cycle. Metaphase cells show frequent chromatid breaks, defined as chromatid discontinuities or terminal deletions, if irradiated in the G 2 -phase of the cell cycle. It has been shown that the frequency of chromatid breaks in cells from approximately 40% of sporadic breast cancer patients, are significantly higher than in groups of normal individuals. This suggests that elevated radiation-induced chromatid break frequency may be linked with susceptibility to breast cancer. It is known that chromatid breaks are initiated by a double strand break (DSB), but it appears that the two are linked only indirectly as repair kinetics for DSBs and chromatid breaks do not match. Therefore, the underlying causes of the wide variation in frequencies of chromatid breaks in irradiated T-lymphocytes from different normal individuals and from sporadic breast cancer cases are still unclear but it is unlikely to be linked directly to DSB rejoining. My research has focused on the mechanism through which chromatid breaks are formed from initial DSBs. The lack of a direct association suggested that a signalling process might be involved, connecting the initial DSB and resulting chromatid break. The signal model, suggested that the initial DSB is located within a chromatin loop that leads to an intra- or interchromatid rearrangement resulting in incomplete mis-joining of chromatin ends during the decatenation of chromatids during G 2 . It was therefore proposed that topoisomerase II alpha (topo IIα) might be involved, mainly because of its ability to incise DNA and its role in sister chromatid decatenation. During my PhD research I have used a strategy of altering topo II activity or expression and studying whether this alters IR-induced chromatid break frequency. The first approach involved cell lines that varied in topo IIα expression. The frequency of IR-induced chromatid breaks was found to correlate positively with topo IIα expression level, as measured in three different cell lines by immunoblotting, i.e. two cell lines with lower topo IIα expression exhibited lower chromatid break frequency. Topo II activity in these three cell lines was also estimated indirectly by the ability of a topo IIα poison to activate the G 2 /M checkpoint, and this related well with topo IIα expression. A second approach involved ‘knocking down’ topo IIα protein expression by silencing RNA (siRNA). Lowered topo IIα expression was confirmed by immunoblotting and polymerase chain reaction. SiRNA-lowered topo IIα expression correlated with a decreased IR-induced chromatid break frequency. In a third series of experiments cells were treated with ICRF-193, a topo IIα catalytic inhibitor. It was shown that inhibition of topo IIα also significantly reduced IR-induced chromatid breaks. I also showed that lowered chromatid break frequency was not due to cells with high chromatid break frequencies being blocked in G 2 as the mitotic index was not altered significantly in cells with lowered topo IIα expression or activity. These experiments show that topo IIα is involved in IR-induced chromatid break formation. The final experiments reported here attempted to show how topo II might be recruited in the process of forming IR-induced chromatid breaks. Hydrogen peroxide was used as a source of reactive oxygen species (reported to poison topo IIα) and it was shown that topo IIα under these conditions is involved in the entanglement of metaphase chromosomes and formation of chromatin ‘dots’ as well as chromatid breaks. Experiments using atomic force microscopy attempted to confirm these dots as excised chromatin loops. The possible role of topo IIα in both radiation- and hydrogen peroxide-induced primary DNA damage was also tested. It was shown that topo IIα does not affect radiation-induced DSBs, even though it does affect chromatid break frequency. Also, topo IIα does not affect hydrogen peroxide-induced DNA damage at low doses. The results support the idea that topo IIα is involved in the conversion of DSBs to chromatid breaks after both irradiation and treatment with hydrogen peroxide at a low concentrations. I have demonstrated that topo IIα is involved in forming IR-induced chromatid breaks, most likely by converting the initial DSBs into chromosomal aberrations as suggested by the signal model.
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Fournel, Ludovic. "Influence Du Cisplatine sur l'expression du Check-Point Immunitaire PD-1/PD-L1 Dans Le Cancer Broncho-Pulmonaire Non A Petites Cellules Cisplatin Increases PD-L1 Expression and Optimizes Immune Check-Point Blockade in Non-Small Cell Lung Cancer Modulation of Lung Cancer Cell Plasticity and Heterogeneity with the Restoration of Cisplatin Sensitivity by Neurotensin Antibody." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS077.
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Malgré les nombreux progrés réalisés ces dernières années dans la prise en charge thérapeutique du cancer broncho-pulmonaire, cette pathologie reste la première cause de décès lié au cancer dans le monde. L’enjeu majeur pour cette maladie est donc de développer de nouveaux traitements et d’optimiser l’utilisation des drogues existantes, en particulier les sels de platine. Les protocoles combinant des inhibiteurs de points de contrôle immunitaire avec des sels de platine est actuellement en plein essor malgré un certain manque en études précliniques. Dans ce travail, j’ai cherché à évaluer l'impact du cisplatine sur l'expression de PD-L1 en analysant des patients ayant reçu une chimiothérapie néo-adjuvante à base de cisplatine. Le traitement d'induction augmentait considérablement le marquage PD-L1 des cellules tumorales et immunitaires du microenvironnement. Vingt-deux patients présentaient une variation positive du pourcentage de cellules tumorales PD-L1+ après chimiothérapie néoadjuvante; dont 9 (23,1%) passant de <50% à ≥50% des cellules tumorales marquées. Nous avons également confirmé la régulation positive de PD-L1 par le cisplatine, tant au niveau de l'ARNm qu’au niveau protéique, in-vitro et in-vivo sur des souris nude et des souris immunocompétentes greffées par des tumeurs expérimentales issues de lignées cellulaires de cancer du poumon A549, LNM-R ou LLC1. L’up-régulation de PD-L1 par le cisplatine fait intervenir la voie de signalisation PI3K/AKT. De plus, l'administration combinée d'anticorps anti-PD-L1 (3 mg / kg) et de cisplatine (1 mg / kg) à des souris portant un carcinome pulmonaire réduisait significativement la croissance tumorale par rapport aux traitements en monothérapie et par rapport aux contrôles. Le cisplatine augmente donc précocément et durablement l'expression de PD-L1 et pourrait donc agir de manière synergique avec un blocage de PD-1 / PD-L1 pour améliorer la réponse tumorale aux traitements. En parallèle, nous avons pu développer une thérapie ciblée anti-neurotensine permettant de bloquer ses effets paracrines stimulants la prolifération, la croissance, et les capacités d’invasion des cellules de tumeurs pulmonaires. Les anticorps anti-neurotensine amélioraient également la sensibilité au cisplatine de tumeurs préalablement résistantes par des mécanismes qui impliquent probablement l’augmentation de l’influx et la diminution de l’efflux de platine au niveau de sa cible intra-nucléaire qu’est l’ADN. L’ensemble de ces résultats apportent du rationnel à la réalisation d’essais cliniques impliquant le cisplatine et visant par différents biais à améliorer l’efficacité de traitements systémiques de cancers broncho-pulmonaires non à petites cellules<br>Despite many advances in the recent years in the therapeutic management of bronchopulmonary cancer, it remains the leading cause of death linked to cancer in the world. The major challenge for this disease is therefore to develop new treatments and optimize the use of existing drugs, in particular platinum salts. The number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from <50% to ≥50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. Up-regulation of PD-L1 by cisplatin involved the PI3K / AKT signaling pathway.The combined administration of anti-PD-L1 antibodies (3mg/kg) and cisplatin (1mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression. Simultaneously, we were able to develop a targeted anti-neurotensin therapy to block its paracrine effects which stimulate proliferation, growth, and metastatic potential of lung tumor cells. Anti-neurotensin antibodies also improved the sensitivity to cisplatin of previously resistant tumors by mechanisms which probably involve increased influx and decreased efflux of platinum at the intra-nuclear level where resides its target DNA. All of these results provide a rationale for carrying out clinical trials involving cisplatin and aiming, by various ways, to improve the effectiveness of systemic treatments for non-small cell broncho-pulmonary cancers
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Engel, Roxane. "The nuclear export of DNA topoisomerase iialpha in hematological myeloma cell lines as a function of drug sensitivity : clinical implications and a theoretical approach for overcoming the observed drug resistance /." [Tampa, Fla.] : University of South Florida, 2005. http://purl.fcla.edu/fcla/etd/SFE0001358.
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Langlands, Fiona Elizabeth. "Sensitivity to radiotherapy in breast cancer." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.582111.
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Radiotherapy (RT) is a component of treatment for breast cancer in more than 50% of cases. Patients are selected for RT on the basis of limited clinical and histopathological factors with no reference to the molecular phenotype of tumours. Breast cancer is a highly heterogeneous disease and some tumours are refractory to RT treatment. Selection of patients for RT using predictive markers may improve RT efficacy and cancer outcomes. The aims of the work described in this thesis were to identify and test potential predictive markers for RT in cancer treatment. I examined whether the classic histopathological breast cancer subtypes or the levels of expression of five molecular markers, 26S proteasome, GRP78, HJURP, IGFlR and PARPl, would provide predictive insights into response to RT in the context of both cultured breast cancer cell lines, and archival patient samples supported by clinical follow up. Clonogenic survival assays revealed that cell lines representative of luminal or basal breast cancers did not display subtype specific responses to RT. Similarly, expression levels of 26S proteasome, GRP78, HJURP, IGFlR and PARPl did. not correlate with specific responses to RT in cell lines. In breast cancer patients who underwent RT high expression of 26S proteasome was significantly associated with increased rates of local recurrence. High expression of HJURP was associated with reduced rates of local recurrence, as was high expression of PARPl. Importantly, these associations were not found in patients who were treated without RT, suggesting that these markers provide predictive in sights into RT response, rather than prognostic insights into the likelihood of local recurrence overall. Finally, high expression of 26S proteasome was also found to be associated with increased rates of local recurrence in bladder cancer patients, suggesting that this marker may have predictive value for RT in a range of cancer settings.
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Chang, Sue-Ling. "Breast cancer subtypes and screening mammography sensitivity." Thesis, Université Laval, 2014. http://www.theses.ulaval.ca/2014/30680/30680.pdf.
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Les cancers du sein peuvent être classifiés selon le statut de récepteur d’estrogène (RE), de récepteur de progestérone (RP), de récepteur HER2, ou selon quatre sous-types (Luminal A, Luminal B, HER2-enrichi, Triple-négatif) ayant des propriétés biologiques et cliniques différentes. La sensibilité du dépistage par mammographie pourrait varier selon ces types de cancers mais ceci n’est pas encore clair. L’agressivité de la tumeur, mesurée par le grade histologique pourrait expliquer cette association. Les types de cancers d’intervalle ont été comparés à ceux de cancers détectés par dépistage parmi 1536 cas infiltrants provenant d’un centre de référence de Québec. Les tumeurs RE-négatif, RP-négatif, HER2-positif, Luminal B, HER2-enrichi et TPN étaient tous plus fréquentes chez les femmes avec cancers d’intervalle que chez celles avec cancers détectés par dépistage. À l’exception des tumeurs HER2-positif et HER2-enrichi, le grade histologique expliquait en grande partie la variabilité observée entre les types de cancer et la sensibilité.<br>Breast cancers can be classified according to tumour estrogen (ER) and progesterone (PR) receptors, human epidermal growth factor receptor 2 (HER2), and according to four subtypes (Luminal A, Luminal B, HER2-enriched, Triple-negative), each with different biological and clinical profiles. These tumour types may also influence screening mammography sensitivity but this is still not clear. Tumour aggressiveness, measured by the histological grade, may also play a role in explaining this association. Interval cancer types were compared to screen-detected cancer types in 1536 invasive cases obtained from a reference center in Quebec. ER-negative, PR-negative and HER2-positive, Luminal B, HER2-enriched and TPN tumours were all more frequent in women with interval cancers than in women with screen-detected cancers. Except for HER2-positive and HER2-enriched tumours, histological grade explained most of the variability observed between tumour receptor status, subtypes and sensitivity.
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Uzzell, Valerie Joy. "Sensitivity and noise in primate retinal ganglion cells /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3190165.
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Lincoln, Maximilian Christian. "Multidrug resistance and collateral sensitivity of tumour cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0018/MQ37141.pdf.
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Coulson-Gilmer, Camilla Lucette. "Cancer stem cells and chemoresistance in ovarian cancer." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/18470/.
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The high mortality rate associated with epithelial ovarian cancer (EOC) is due to its insidious onset, leading to late diagnosis as well as eventual development of chemoresistance in the majority of patients. Cancer stem-like cells (CSCs) are thought to contribute to development of multi-drug resistant (MDR) tumours partly through their high level of ABC-transporter expression, which enables them to survive chemotherapy. ABC-transporter (MRP1, MRP2, BCRP, Pgp) and putative CSC-marker (ALDH1A1, CD44) expression was therefore evaluated by immunohistochemistry in a paraffin-embedded cohort of 57 high-grade EOC tumours. Typically 9-12% of cells in tumours expressed CD44 / ALDH1A1. These may represent a population enriched for CSCs. ABC-transporters were expressed in 10- 43% of cells on average. Using Spearman rank test, there was no correlation between CSC- marker and ABC-transporter expression, however correlation was observed between many of the ABC-transporters, suggesting existence of highly drug-resistant populations within tumours. Expression of CA125 (a glycoprotein expressed by EOC cells and used clinically to detect EOC relapse) and EpCAM (a cell adhesion molecule expressed by EOC cells) was also investigated. Interestingly, patient tumours with the highest level of EpCAM had longer overall survival by Kaplan-Meier analysis. In addition, increased expression of MRP1 and CD44 predicted poorer patient outcome by Cox regression analysis. In vitro functional assays were also used to identify CSCs. Cells derived from ascites samples had a mean colony-forming efficiency (CFE) or 6.3%, and in unsorted tumours this was 11.4%. Cancer cells were then isolated from primary ascites and tumour samples (using CA125 and EpCAM). On average, self-renewing assays revealed a 2.2-2.4-fold increase in CFE for CA125 or EpCAM positive sorted cells compared to CA125 or EpCAM negative cells. Future studies could characterise these self-renewing populations, which may lead to identification of novel CSC targets for use in EOC treatment.
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Drayton, Ross. "Drug sensitivity and apoptosis in tamoxifen resistant breast cancer." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/55694/.
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Tamoxifen has long been used in the treatment of hormone responsive breast cancer. However, tumours frequently develop resistance within 2-5 years of treatment, characterised by the return of tumour growth. The epidermal growth factor receptor EGFR is an important contributing factor in allowing formerly tamoxifen sensitive tumours to grow in the presence of tamoxifen. High levels of EGFR in many tumours correlate with a poor prognosis and an increased resistance to cytotoxic drugs. It was the initial aim of this study to ascertain whether the increased EGFR signalling associated with tamoxifen resistance results in a phenotype more resistant to cytotoxic drugs, and to study the underlying mechanisms that may cause this. Rather than observing the expected increase in resistance to cytotoxic drugs upon the development of tamoxifen resistance, a greatly increased sensitivity to the radiomimetic drug bleomycin was observed. Inhibition of EGFR in either the tamoxifen sensitive or resistant cells had very little effect on bleomycin sensitivity, The rate of uptake of various drugs was measured, and found to be identical between tamoxifen sensitive cells and their tamoxifen resistant derivatives. Microarray analysis of mRNA levels of drug efflux proteins also showed no significant decrease in drug efflux pump gene expression, with two efflux pump genes MRP3 and MRP4 showing increased expression. Tamoxifen resistant cells displayed greatly increased sensitivity to the apoptosis inducer camptothecin, and showed a significant increase in the levels of activated caspases present. Immunocytochemistry revealed a significant downregulation of the anti-apoptotic protein bcl-2.. Sensitivity to bleomycin was also measured and was found to inversely correlate to bcl-2 status. Finally bcl-2 levels were modulated using oestrogens and antioestrogens, and with an siRNA directed against the oestrogen receptor. The effect on bleomycin sensitivity was examined. Reduction of bcl-2 expression by either method had no effect on bleomycin sensitivity
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Múnera, Jorge O. "Ets2 regulates colonic stem cells and sensitivity to tumorigenesis." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3397225.
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Thesis (Ph. D.)--University of California, San Diego, 2010.<br>Title from first page of PDF file (viewed March 30, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 101-108).
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Chan, Ching Wan. "Apoptosis in breast cancer cells." Thesis, University of Bristol, 2004. http://hdl.handle.net/1983/8971525c-0de9-4e21-9677-ab73d61ae65c.
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Sherwood, Benedict T. "Radiosensitivity in bladder cancer cells." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29874.
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Potentially curative treatment options for patients with organ-confined transitional cell carcinoma (TCC) of the bladder (T1-4a/N0/M0) are radical cystectomy or radiotherapy (RT)-based 'bladder-preserving' regimens. A substantial number of patients who receive RT fail to respond (approximately 50%). Consequently, a greater understanding of the mechanisms of radioresistence is required, together with predictive information regarding the response of tumours to RT. Hypoxia and intrinsic cellular Radiosensitivity (IRS) are examined here, a factors that may influence the outcome of RT.;An immunohistochemical assay using hypoxia-related carbonic anhydrase IX (CA IX) was undertaken to determine the prognostic significance of hypoxia in bladder tumours treated with RT. A modified version of the alkaline comet assay (ACA) was used to examine differences in IRS between cells derived from TCC specimens. Nuclear factors that influence comet formation (and therefore radiosensitivity) were also examined, such as DNA double strand break (DSB) rates and differences in nuclear matrix protein (NMP) composition.;CA IX immunostaining did not provide prognostic information with respect to response to radical RT. ACA analysis indicated a wide range of responses between tumours. In TCC cell lines, DSB rates are not demonstrably different in cells of differentiated radiosensitivity, however, comparative analysis of nuclear proteins identified differences in their constitutive NMPs and repair enzymes.;These results do not provide evidence that hypoxia influences outcome after RT, but support the contention that ICR is important in dictating the response of bladder tumours to RT. Furthermore, in bladder cancer cell lines of differing radiosensitivity, differences in NMP and repair enzymes are identified. Further work is required to determine whether these are of prognostic importance.
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Fung, Kwong-lam, and 馮廣林. "Chemoresistance induced by mesenchymal stromal cells on cancer cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205639.
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Human mesenchymal stromal cells (hMSCs) are part of bone marrow micro-environment that supports hematopoiesis. However, hMSCs also enhance tumor progression and survival when they become part of the cancer micro-environment. I aimed to investigate the interaction between hMSCs and cancer cells during chemotherapy.
Firstly, I studied the interaction between hMSCs and T-lineage acute lymphoblastic leukemia (T-ALL) cells under pegylated arginase I (BCT-100) treatment. Three T-ALL cell lines were sensitive to BCT-100 but not hMSCs. Conversely, hMSCs could partly protect all T-ALL cell lines from BCT-100 induced cell death under transwell co-culture condition. Concerning the possible mechanism, the intermediate metabolite L-ornithine could not rescue most T-ALL cells from BCT-100 treatment. But the downstream L-arginine precursor, L-citrulline could partly rescue all T-ALL cells from BCT-100 treatment. Ornithine transcarbamylase (OTC) converts L-ornithine into L-citrulline. OTC expression level in hMSCs remained relatively high during BCT-100 treatment but OTC expressions in T-ALL cell lines declined drastically. It suggested that hMSCs may protect T-ALL cells against BCT-100 treatment by having sustained OTC expression. Suppression of hMSCs by vincristine (VCR) disrupted the protective effect of hMSCs to most T-ALL cells during BCT-100 treatment. This suggests that by transiently suppressing hMSCs, we may abolish the protective effect of hMSCs to T-ALL cells during BCT-100 treatment.
Then I studied the interaction between hMSCs and neuroblastoma under cisplatin treatment. Two neuroblastoma cell lines were used for both of them are cisplatin sensitive while hMSCs are cisplatin resistant. hMSCs could partly protect neuroblastoma cells from cisplatin induced cytotoxicity. On the other hand, exogenous IL-6 but not IL-8 could also partly rescue them from cisplatin induced cytotoxicity. IL-6 activated STAT3 phosphorylation dose-dependently and enhanced expression of detoxifying enzyme (glutathione S-transferase π, GST-π) in neuroblastoma. Such effect could be counteracted by anti-IL-6R neutralizing antibody tocilizumab (TCZ). However, TCZ failed to suppress hMSCs’ protection to neuroblastoma during cisplatin treatment. This suggests involvement of multiple factors. Up-regulation of serum GST-πin some hTertMSCs/neuroblastoma co-engrafted SCID mice compared to neuroblastoma engrafted mice provided a clue that GST-π might be a possible stromal-protection factor. Caffeic acid phenethyl ester (CAPE) is a known GST inhibitor after tyrosinase activation. Neuroblastoma cells expressed tyrosinase and CAPE enhanced cisplatin cytotoxicity on them, with or without hMSCs. Paradoxically, CAPE enhanced GST-πexpression with or without cisplatin treatment in neuroblastoma suggesting possible negative feedback to GST-π inhibition. However, such additive effect of CAPE to cisplatin cytotoxicity was not observed in vivo. Further delineation of the in vivo study design may help to verify the additive effect of CAPE to cisplatin cytotoxicity in vivo.
Finally, I studied the effect of apoptotic cancer cells (AC) on the immune function of hMSCs. hMSCs could phagocytose apoptotic neuroblastoma cells with respective up-regulation of many immune-mediators including two highly-expressed cytokines IL-6 and IL-8. Up-regulation of these immune-mediators may enhance immune cells chemotaxis. Further detailed investigation on the effect of AC-engulfed hMSCs to other immune cells will help us to understand the dynamic interaction between cancer cells and stromal cells during chemotherapy.<br>published_or_final_version<br>Paediatrics and Adolescent Medicine<br>Doctoral<br>Doctor of Philosophy
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Grero, Dhanya. "Cytotoxicity of Vγ9Vδ2 T cells towards Colon Cancer Cells". Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-230976.
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Immunotherapies for cancer are widely studied at present. We are currently studying a specific form of “Vγ9Vδ2 T cells” found in the peripheral blood of healthy donors that can be used for the killing of HT-29 colon cancer cells. In order to determine the cytotoxicity of effectors, Vγ9Vδ2 T cells towards target cells, HT-29, it is important to first evaluate the absolute number of Vγ9Vδ2 T cells in a mixed cell population, and next to determine the phenotypic characterization, their activity and cytotoxicity in the presence of target cells. A flow cytometry and bead based assay was developed to evaluate the absolute number of Vγ9Vδ2 T cells in a mixed cell population. Peripheral Blood Mononuclear Cells (PBMCs) were surface stained with monoclonal antibodies (MoAbs) conjugated to fluorochromes that are cross reactive to cell surface markers such as CD3 (T Lymphocytes), γδ2 and were mixed with fluorophore beads. In these assays, no washes and centrifugation steps were performed after the cell surface staining and bead addition. The absolute cell counts were evaluated based on referencing a known concentration of beads. In addition, quantification assays were also performed to measure the cell and bead loss on surface staining that included washes and centrifugation steps and thus found a higher percentage loss of cells than beads. Immunophenotyping assays with four color staining were performed to monitor the phenotypic differentiation of effector cells based on cell surface markers CD27 and CD45RA. Only the naïve (CD27+CDRA+) and terminally differentiated effector memory (CD27-CD45RA+) were identified on the assays performed using Vγ9Vδ2 T cells of different donors. A flow cytometry based cytotoxicity (FCC) assay was completed to monitor the effector cell activity (CD69+) in the presence and absence of target cells and also the cytotoxicity was measured based on % specific lysis of target cells at four different effector to target (E:T) cell ratios. Only preliminary data were obtained for the FCC assay and the development is still in progress.
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Briggs, Clare. "An investigation into ultraviolet radiation sensitivity and human skin cancer." Thesis, Lancaster University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403927.
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Kelly, J. D. "In vitro sensitivity of superficial bladder cancer to Mitomycin-C." Thesis, Queen's University Belfast, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403682.
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Howard, S. J. "Sensitivity to UV-damage in SV40-transformed Indian muntjac cells." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604272.
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SVM87, is an SV40-transformed Indian muntjac cell line which has previously been shown, in comparison with a spontaneously transformed but non-isogenic cell line DM, to be unusually sensitive to UV-irradiation. UV-sensitivity cannot be explained by a difference in DNA repair capacity. In this dissertation work we have found that SV40-transofrmation is the cause of the SVM87 phenotype. Over seven independent SV40-transformed Indian muntjac cell lines have been examined and all shown to be sensitive to UV-damage, to the same extent as SVM87. Flow cytometry studies show that the sensitivity results from an inability of these cells to effectively replicate UV-damaged DNA. The cells exhibit slow S-phase progression, severe genomic instability and cell death following UV-irradiation. Examination of DNA replication intermediates, following UV-irradiation, show that single stranded DNA regions, containing UV-photoproducts, persist within the nascent fraction for extended periods of time in UV-sensitive, but not normal cell lines. In an attempt to identify the basis for this SV40 T-constructs was generated and examined. The results indicate that the critical region of the T-antigen for establishing the UV-sensitive phenotype resides within the N-terminus 147 amino acids for T-antigen. This region includes p300, polymerase α-primase and pRb binding domains.
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Yang, Chun-ting, and 楊俊廷. "The role of stroma cells in radio-sensitivity of cervical cancer HeLa cells." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/75069684690592311309.
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碩士<br>慈濟大學<br>分子生物暨人類遺傳學系碩士班<br>99<br>Radiotherapy is one of effective treatments for patients with cervical cancers, especially for those with direct invasion or distal metastasis. However, outcome of radiotherapy is not consistent. In this study, role of stromal cells in radio-sensitivity of cervical cancer HeLa cells cultured in condition media (CMs) derived form coculture of HeLa cells and stromal cells were investigated. To prepare conditioned media from stromal cells or mixcultures (Stromal cells : HeLa cells = 1:1), stromal cells prepared from stromal cells closed to the cervical tumor were described as Sn, or those farther away from cervical tumor were described as Sf. HeLa cells were cultured in CMs derived from stromal cells or HeLa/stromal coculture for 4 hours then irradiated at 8Gy. Those CMs could increase proliferation and cell survival of HeLa cells after 8Gy irradiation.
Quantitative PCR (qPCR) revealed that expression of DNA damage repair gene, BTG2 was up-regulated gradually at 8hours and 24hours, and apoptosis gene, GADD45α was down-regulated at 8hours and 24hours after 8Gy radiation when HeLa cells were treated with CMs from mixSn and mixSf.
These results suggest that SnCM and SfCM may support DNA damage repair in HeLa cells irradiated with 8 Gy. MixSn and mixSf CMs may reduce apoptosis in HeLa cells with DNA damage. Protein antibody array indicated the presence of HGF, EGF, IGFBP-2 and IGFBP-4 in CMs derived from culture Sn and mixSn, and IGFBP-3 and PDGF-AA was up-regulated in mixSnCM. Phosphorylation of MAPKp38 (mitogen activated protein kinases) was upregulated at 2 and 4 hours in SnCM and mixSnCM.
In conclusion, cytokines such as IGFBP-3 in mixSnCM may regulate the phospho-p38 and decrease DNA damage in HeLa cells to avoid cell death after irradiation, therefore, increase proliferation and colony formation.
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Chang, Chia-Shuo, and 張家碩. "Enhancement of radio-sensitivity in prostate cancer stem cells by bacterial genotoxin." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/39565792960172029794.
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碩士<br>中國醫藥大學<br>基礎醫學研究所碩士班<br>100<br>Prostate cancer (PCa) is one of the most malignancies in male in western developed countries and its incidence is rising in Taiwan. Although most patients can be cured by surgery and radiotherapy, more than 30,000 patients were died of the disease in the United States annually. Ionizing radiation (IR) is employed frequently in the management of several tumor types, including advanced PCa. DAB2IP (DOC-2/DAB2 interactive protein) is a potent growth inhibitor for PCa by inducing apoptotic pathway. By knocking down endogenous DAB2IP levels, PCa cells become resistance to IR-induced apoptosis. Our results showed that cytolethal distending toxin (CDT), a genotoxin which produced by Campylobacter jejuni, converted radio-resistance to susceptible phenotype. Combined treatment of CDT and IR induced cell death through ATM-dependent DNA damage checkpoint responses in radio-resistant PCa. Moreover, CDT significantly enhanced IR-induced tumor growth delay was observed in an animal experimental model. These findings indicate that CDT can be administered with IR to overcome radio-resistant PCa, particularly in DAB2IP-deficient phenotype.
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HUANG, JING-MIN, and 黃經民. "Characteristics of semipermeable microcapsule culture for cancer cells and amticancer sensitivity assay." Thesis, 1988. http://ndltd.ncl.edu.tw/handle/85040222747335977359.
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Fernandes, Andreia Silva. "Cancer cells: a crosstalk between general metabolism and sensitivity to apoptotic signals." Master's thesis, 2017. http://hdl.handle.net/10348/8800.
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The transformation of a normal cell into a cancer cell is a pathological process involving several stages, which modifies cellular metabolism and supports: rapid generation of ATP, high rate of macromolecules biosynthesis and maintenance of the appropriate cellular redox state. Mitochondria play a central role in the eukaryotic cell because of their relevance in biosynthetic and bioenergetic metabolisms. Additionally, mitochondria are also responsible for the production and/or control of various types of signals (including molecules), involved in cellular signalling processes that modulate various aspects of the functional organization of cells and their interaction with neighbouring cells. For example, this organelle is particularly associated with the processes of cell death by apoptosis. In this context, the development and progression of oncologic disease is inevitably associated with changes in metabolic pathways/signalling that involve mitochondria. Two models of human cancer cells, notably A549 cells (representative of non-small cell lung cancer) and AGS cells (representative of stomach cancer promoted by intestinal type cells), are used in the present work to investigate the relationship between metabolic parameters and sensitivity of cancer cells to apoptotic stimuli. This aspect is fundamental to understanding the mechanisms used by cancer cells to develop resistance to conventional chemotherapy and also to develop new and more effective therapeutic strategies. The results obtained show that these two cell lines show distinct profiles of growth curves. The cell proliferation rate (inversely proportional to the doubling time) of A549 cells is slightly higher than AGS cells. However, when compared to A549 cells, AGS cells exhibit higher intracellular glycogen content, higher MTT reduction ability and much higher mitochondrial functionality, as revealed by the parameters that characterize mitochondrial respiration (basal respiration, respiration associated with synthesis of ATP and maximum breathing capacity). Additionally, the lipid composition of the membranes of these cells also depends on the cell type. When normalized by the amount of protein, A549 cells exhibit higher lipid content (phospholipids + cholesterol) but lower glycolipid content than AGS cells. Analysis of the fatty acid profiles revealed that A549 cells exhibit lower relative abundance of saturated fatty acids, higher abundance of monounsaturated fatty acids and a higher ratio of Omega6/Omega-3 polyunsaturated fatty acids to those of AGS cells. The characterization of the oxidation-reduction cell state was evaluated by the GSH/GSSG ratio. The activity of the enzymatic antioxidant defences and the rate of production of reactive oxygen species follow a pattern consistent with the metabolic differences presented by the two cell lines. Thus, AGS cells exhibit Catalase and Superoxide dismutase (SOD) activities superior to A549 cells, despite their r viii intracellular compartments are, in average, a more oxidized state, as suggested by the lower ratio GSH/GSSG. Notwithstanding these differences, the ROS production rate is similar in both cell lines. Considering the effect of increasing concentrations of staurosporine on cell viability, AGS cells (IC50 = 20.5 nM) are shown to be significantly more sensitive than the A549 cells (IC50 = 108.0 nM) to this apoptotic agent. Staurosporine, at the concentration of IC50 for each cell line, promotes a significant decrease in the electrical potential across the mitochondrial inner membrane (ΔΨm) in both cell lines without affecting ROS generation. Additionally, the A549 cell line was shown to exhibit ΔΨm significantly higher than the AGS cell line, exhibiting more hyperpolarized mitochondria. The impact of the destruction of the extracellular matrix (through trypsin activity) in the oxidationreduction cell, ΔΨm and ROS production was also evaluated in both cell lines. The trypsinization process destroys the extracellular matrix and transforms adherent cells into mobile/floating cells, promoting in both cell lines a significant increase in ROS production. These effects are more evident in A549 cells. The increase in ROS production rate is accompanied by a decrease in the GSH/GSSG ratio and an increase of ΔΨm; and again, these effects are also more evident in A549 cells. Together, the results support the idea that the higher tumour aggressiveness of A549 cells, compared to AGS cells, detected by the higher rate of cell proliferation and the greater the ability to evade apoptosis (less sensitivity to staurosporine) are reflex of the glycolytic phenotype. This phenotype is characterized by hyperpolarized mitochondria, lower respiratory activity and supported by a lower intracellular environment. Moreover, A549 cells showed their membrane lipids with superior abundance of monounsaturated fatty acids and higher omega-6/omega-3 ratio. At last, when the cells are no longer bound to the extracellular matrix, mimic by trypsinization process, their mitochondria becomes more hyperpolarized, ROS production increases and their intracellular environment becomes more oxidized, increasing their tumour aggressiveness.<br>A transformação de uma célula normal numa célula cancerosa é um processo patológico que ocorre simultaneamente em várias etapas. Estas alterações ocorrem de forma a modificar o metabolismo celular assegurando a rápida produção de ATP, a alta taxa de biossíntese de macromoléculas e a manutenção do estado redox celular. A mitocôndria desempenha um papel central na célula eucariota, pela sua relevância nos metabolismos biossintético e bioenergético. Adicionalmente, as mitocôndrias são também responsáveis pela produção e/ou controlo de vários tipos de sinais (incluindo moléculas) envolvidos nos processos de sinalização celular que modulam vários aspetos da organização funcional das células, incluindo a sua interação com células vizinhas. Por exemplo, este organelo está particularmente associado aos processos de morte celular por apoptose. Neste contexto, o desenvolvimento e a progressão da doença oncológica está inevitavelmente associada com alterações nas vias metabólicas/sinalização que envolvem a mitocôndria. Dois modelos de células de cancro humano, nomeadamente células A549 (representativas de carcinoma do pulmão ligado às células “não pequenas”) e células AGS (representativas do cancro do estômago promovido por células do tipo intestinal), são usados no presente trabalho para investigar a relação entre parâmetros metabólicos e a sensibilidade das células cancerosas a estímulos apoptóticos. Este aspeto é fundamental para compreender os mecanismos usados pelas células cancerosas para desenvolver resistência à quimioterapia convencional e também para desenvolver novas estratégias terapêuticas mais eficazes. Os resultados obtidos mostram que estas duas linhas celulares apresentam curvas de crescimento distintas, sendo a taxa de proliferação celular (inversamente proporcional ao do tempo de duplicação) das células A549 ligeiramente superior à das células AGS. Todavia quando comparadas com as células A549, as células AGS apresentam maior conteúdo intracelular de glicogénio, exibem maior capacidade de redução do MTT e exibem uma funcionalidade mitocondrial muito superior, como é mostrado pelos parâmetros que caracterizam a respiração mitocondrial (respiração basal, respiração associada com a síntese de ATP e capacidade máxima de respiração). Adicionalmente, a composição lipídica das membranas destas células também é dependente do tipo de célula. Quando normalizado pela quantidade de proteína, as células A549 apresentam maior conteúdo lipídico (fosfolípidos + colesterol) mas menor teor de glicolípidos do que as células AGS. A análise dos perfis de ácidos gordos revelou que as células A549 apresentam menor abundancia relativa de ácidos gordos saturados, maior abundancia de ácidos gordos monoinsaturados e uma razão de ácidos gordos polinsaturados Omega-6/Omega-3 superior às das células do AGS. A caracterização do estado de oxidação-redução das células (avaliado pela razão GSH/GSSG), da atividade das defesas antioxidantes enzimáticos e da taxa de produção de espécies reativas de oxigénio mostrou que estes parâmetros seguem um padrão consistente com as diferenças metabólicas apresentadas pelas duas linhas celulares. Assim, as células AGS apresentam uma atividade dos dois tipos de sistemas enzimáticos, Catalase e Superóxido dismutase (SOD), superior à das células A549, apesar de, em média, os seus compartimentos intracelulares estarem num estado mais oxidado, como sugerido pela menor razão GSH/GSSG. Apesar destas diferenças, a taxa de produção ROS é semelhante em ambas as linhas celulares. Considerando o efeito de concentrações crescentes de staurosporina na viabilidade celular, mostrou-se que as células AGS (IC50 = 20,5 nM) são significativamente mais sensíveis do que as células A549 (IC50 = 108,0 nM) a este agente apoptótico. A staurosporina, à concentração do IC50 para cada linha celular, promove em ambas as linhas celulares uma diminuição significativa do potencial elétrico através da membrana interna mitocondrial (ΔΨm) sem afetar a geração de ROS. Adicionalmente, mostrou-se também que a linha celular A549 exibe um ΔΨm significativamente maior do que a linha celular AGS, apresentando estas células mitocôndrias mais hiperpolarizadas. O impacto da destruição da matriz extracelular (através da atividade da tripsina) no estado de oxidaçãoredução celular, no ΔΨm e na produção de ROS foi também avaliado em ambas as linhas celulares. O processo de tripsinização destrói a matriz extracelular e transforma células aderentes em células móveis/flutuantes, promovendo, em ambas as linhas celulares, um aumento significativo na produção de ROS; sendo os efeitos mais evidentes nas células A549. O aumento da taxa de produção de ROS é acompanhado pela redução da razão GSH/GSSG e por um aumento do ΔΨm, sendo estes efeitos também mais evidentes nas células A549. Em conjunto, os resultados obtidos suportam a ideia de que a maior agressividade tumoral das células A549, em comparação com células AGS, detetadas pela maior taxa de proliferação celular e pela maior capacidade de evasão à apoptose (menor sensibilidade à staurosporina) são reflexo do seu fenótipo glicolítico. Este fenómeno glicolítico é caracterizado por mitocôndrias hiperpolarizadas e com menor atividade respiratória, suportadas também por um ambiente intracelular menos reduzido e lípidos membranares com maior abundancia de ácidos gordos monoinsaturados e maior razão ómega-6/ómega3. Adicionalmente, quando as células deixam de estar ligadas à matriz extracelular, processo de tripsinização, a sua mitocôndria torna-se mais hiperpolarizada, a produção de ROS aumenta e o seu ambiente intracelular torna-se mais oxidado, aumentando a sua agressividade tumoral.