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Cao, Siyu. "Designer bacteria as anti-cancer agents." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/366498.
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To date, cancer persists as one of the most devastating diseases worldwide. Problems such as inoperable primary tumours due to late stage diagnosis, presence of metastatic tumours, and tumour resistance to chemotherapy and radiotherapy have remarkably limited the therapeutic effects of existing treatments. To address these problems, cancer gene therapy has been under rapid development over the past two decades, which is specifically designed to deliver therapeutic genes to treat cancers using vector systems. However, the lack of an ideal vector has been a major drawback. Recent understanding of hypoxic and necrotic regions within solid malignancies and rapid development of recombinant DNA technology have reignited the idea of using anaerobic bacteria such as Clostridium as novel intra-tumoural delivery systems for anti-cancer therapeutics. These bacterial vectors have unique advantages over other delivery systems and are likely to become the vector of choice for cancer therapy in the near future. At present, Clostridium-mediated cancer therapy has shown some promising therapeutic efficacy against a number of solid malignancies, providing an opportunity for the development of novel anti-cancer gene therapies. In the last decade, targeted cancer therapy has witnessed its most impressive progress. Anti-cancer monoclonal antibodies (mAb) and recombinant immunotoxins against specific tumour cell surface antigens such as epidermal growth factor receptor (EGFR) have shown encouraging therapeutic efficacy against a large spectrum of cancers. However, difficulties such as insufficient intra-tumoural drug delivery have been preventing the therapy from reaching its full therapeutic potentials.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Traore, Mahama Aziz. "Bacteria-Enabled Autonomous Drug Delivery Systems: Design, Modeling, and Characterization of Transport and Sensing." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/64326.
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The lack of efficacy of existing chemotherapeutic treatments of solid tumors is partially attributed to the limited diffusion distance of therapeutics and the low selectivity of anti-cancer drugs with respect to cancerous tissue, which also leads to high levels of systemic toxicity in patients. Thus, chemotherapy can be enhanced through improving anti-cancer drug carrier selectivity and transport properties. Several strains of gram positive (e.g. Clostridium and Bifidobacterium) and gram-negative (e.g. Salmonella Typhimurium and Escherichia coli) bacteria have been shown to possess the innate ability to preferentially colonize tumor tissues. The overall goal of this dissertation is to characterize the transport and sensing of Bacteria-Enabled Drug Delivery Systems (BEADS) in select relevant environments and to investigate the associated underlying principles. BEADS consist of an engineered abiotic load (i.e. drug-laden micro or nano-particles) and a living component (i.e. bacteria) for sensing and actuation purposes. Findings of this dissertation work are culminated in experimental demonstration of deeper penetration of the NanoBEADS within tumor tissue when compared to passively diffusing chemotherapeutic nanoparticles. Lastly, the transport mechanisms that Salmonella Typhimurium VNP20009 utilize to preferentially colonize solid tumors are also examined with the ultimate goal of engineering intelligent and more efficacious drug delivery vehicles for cancer therapy.Ph. D.
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LEPORI, IRENE. "Optimization of attenuated Listeria monocytogenes cell wall chemical engineering to increase its anticancer vaccine activity and to use it as metastasis tracer." Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1072153.
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Attenuated Listeria monocytogenes (Lmat) is widely investigated as anticancer vaccine thanks to its capability to activate host immune-response against the tumour tissues. Lots of genetic engineering strategies have been used to improve its power, such as increasing its immune-stimulation against the cancer tissues by the expression of tumour associated antigens. Since Lmat is capable to selectively accumulate in primary tumours and metastasis, compared with the healthy tissues, we started exploring the possibility of using Lmat as drug carrier and metastasis tracer, by using chemical cell wall modifications that allow us to attach little chemicals onto the bacterial cell wall. In this work we optimized the chemical engineering of Lmat cell wall to let it expose reporter chemical groups, such as alkyne or azido group, that can selectively react with the respective chemical partner (azido and alkyne) by bioorthogonal and bio-compatible “click-reaction”. After comparison of different probes for the functionalization of Lmat cell wall, we optimized the protocol for efficient and totally bio-compatible labelling by using azido-D-alanine probe and both the strain-promoted alkyne-azide cycloaddition (SPAAC) and the copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) reactions. We tested the in vitro features of labelled Lmat and demonstrated that it maintains unaltered proliferative activity, infectivity and intrinsic toxicity effect on 501-mel cell line. We started exploring the chemical conjugation between Lmat and doxorubicin for the drug-carrier strategy, and with Cy7.5 Photoacoustic Dye (PAI) for the metastasis imaging strategy.
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Kandoth, Noufal. "Design, Synthesis and Characterization of Photoactivable Cyclodextrin-Based Nanoparticles for Multimodal Anticancer Therapy." Doctoral thesis, Università di Catania, 2013. http://hdl.handle.net/10761/1280.
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The general goal of this thesis is the development of new generation photoactivable smart nanomaterials that can be modulated into tremendous way to achieve multimodal anticancer and antimicrobial therapeutic actions. Here the cyclodextrins act as the building block for the development of the nanocarrier in order to convey the therapeutic payload to the desired site. With this goal in mind, we have developed several kinds of nanosystems and are discussed in each chapter. The entire dissertation is divided into four sections based on the types of materials and the sections are further divided into twelve chapters based on the functional behavior of each nanosystems.
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Babatunde, Oluwaseun Oyeniyi. "Exploring the potential of Rhodobacter sphaeroides in photodynamic therapy of tumors." Bowling Green State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1624793446693196.
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Babatunde, Oluwaseun Oyeniyi. "Exploring the potential of Rhodobacter sphaeroides in photodynamic therapy of tumors." Bowling Green State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1624793446693196.
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Pahle, Jessica. "Oncoleaking gene therapy: a new suicide approach for treatment of pancreatic cancer." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19298.
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Bakterielle Toxine stellen eine wirkungsvolle und effektive Alternative zur Therapie von Tumorerkrankungen dar. Das vom Clostridium perfringens Typ A produzierte Clostridium perfringens enterotoxin (CPE) gehört zu der Gruppe der porenbildenden Toxine und weist eine rezeptorspezifische zytotoxische Wirkung auf, welche über die Membranrezeptoren Cldn3 und Cldn4 entfaltet wird. Diese liegen vor allem in Epithelialkarzinomen wie dem Brust-, Prostata-, oder Kolon-, sowie dem Pankreaskarzinom (PK) stark hochreguliert vor.
Ziel dieser Arbeit war die Anwendung des neuen selektiven und effizienten „Onkoleaking“ Suizid-Gentherapie Konzepts für die Behandlung von Cldn3 / 4 überexprimierender PK unter Verwendung eines nicht-viralen translations-optimierten CPE exprimierenden Vektors (optCPE). Weiterhin sollte in dieser Arbeit der genaue molekulare Mechanismus der CPE-vermittelten Zytotoxizität in vitro und auch in vivo analysiert werden. Für die in vitro Analysen wurden verschiedene humane PK Zelllinien, Patienten abgeleitete Xenotransplantate (PDX) und deren abgeleiteten Zellen bezüglich ihrer Cldn3 / 4 Expression und Sensitivität sowohl gegenüber rekombinantem CPE (rekCPE) als auch nach optCPE Gentransfer untersucht. Es konnte eine positive Korrelation zwischen der Effizienz CPE vermittelter Zytotoxizität und der Höhe der Cldn3 / 4 Überexpression gezeigt werden. Des Weiteren wurde die Verfügbarkeit und Zugänglichkeit der CPE Rezeptoren für die Toxinbindung als kritischer Faktor für die durch Porenbildung induzierte Zytotoxizität beschrieben. Auch eine detaillierte Analyse verschiedener apoptotischer und nekrotischer Signalwege und deren Schlüsselmoleküle waren vom besonderen Interesse. Von noch größerer Wichtigkeit war jedoch die Anwendbarkeit und der Nachweis der antitumoralen Wirksamkeit der optCPE-basierten Suizid-Gentherapie mit Hilfe des intratumoralen Jet-Injektion Gentransfers in verschiedenen Luziferase-exprimierenden CDX und PDX Modellen des PK. Alle in vivo Studien zeigten eine selektive optCPE vermittelte Verminderung der Tumorvitalität in Verbindung mit Nekrose, die in fast allen Fällen mit einer Reduktion des Tumorvolumens einher ging. Die tierexperimentellen Studien belegen damit die Effektivität der CPE-basierten Gentherapie im Pankreaskarzinom. Mit diesen neu gewonnenen Erkenntnissen zum „Onkoleaking“ Konzept der CPE Suizid-Gentherapie und deren Wirkungsmechanismen sind Kombinationen mit konventionellen Therapien möglich.Bacterial toxins have evolved to an effective therapeutic option for cancer therapy and numerous studies demonstrated their antitumoral potential. The Clostridium perfringens enterotoxin (CPE), produced by the anaerobic Clostridium perfringes bacteria, is a pore-forming (oncoleaking) toxin, which binds to its receptors claudin-3 and -4 (Cldn3 / 4) and exerts a selective, receptor-dependent cytotoxicity. The transmembrane tight junction proteins Cldn3 and Cldn4 are known CPE receptors and are highly upregulated in several human epithelial cancers such as breast, colon, ovarian and pancreatic cancer. This study aimed at the evaluation of the potential of oncoleaking gene therapy using a non-viral translation optimized CPE vector (optCPE) as a new suicide approach for the treatment of Cldn3 / 4 overexpressing pancreatic cancer (PC) in vitro and in vivo. We demonstrated the successful in vitro use of optCPE gene transfer in a panel of human PC cells and more importantly patient derived PC xenograft (PDX) derived cells. We showed significant reduction of cell viability in all Cldn3 / 4 overexpressing PC cells after optCPE transfection. Furthermore a positive correlation between CPE cytotoxicity and level of claudin expression was shown. We revealed accessibility of CPE receptors for toxin binding as determining for optCPE mediated cytotoxicity. Since investigation of optCPE induced cell death mechanism was of particular interest, detailed analyses of apoptotic and necrotic key players were performed. By this, caspase dependent- and independent apoptosis and necrosis activation after gene transfer was demonstrated, which was dependent on amount of expressed optCPE and accessibility of Cldn. More importantly, this study demonstrated the applicability and antitumoral efficacy of optCPE gene therapy by the non-viral intratumoral jet-injection gene transfer in vivo in different luciferase-expressing CDX and PDX pancreatic cancer models. The animal experiments demonstrated the selective CPE mediated tumor growth inhibition, associated with reduced tumor viability and effective induction of tumor necrosis. This further corroborated the advantages of this novel oncoleaking strategy. With this gain of knowledge about our new oncoleaking concept of suicidal gene therapy and its mechanism of action, novel combinations with conventional therapies are possible to further improve therapeutic efficacy and to overcome resistance in pancreas carcinoma.
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Broadway, Katherine Marie. "Novel Perspectives on the Utilization of Chemotactic Salmonella Typhimurium VNP20009 as an Anticancer Agent." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/84898.
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Attenuated bacterial strains have been investigated on the premise of selective tumor colonization and drug delivery potential for decades. Salmonella Typhimurium VNP20009 was derived from the parental strain 14028 through genetic modification and tumor targeting ability, being well studied for anticancer effects in mice. In 2001 Phase 1 Clinical Trials, patients diagnosed with melanoma were introduced with VNP20009, resulting in safe delivery of the strain and targeting to the tumor, however no anticancer effects were observed. Recently, it was discovered that VNP20009 contains a SNP in cheY, which encodes the chemotaxis response regulator of flagellar motor function, rendering the strain deficient in chemotaxis. Replacement of cheY with the 14028 wild-type copy resulted in a 70% restoration of phenotype in traditional chemotaxis capillary assays compared to the parental strain. We attempted to optimize the chemotactic potential of VNP20009 but were unable without reversing the attenuated state of VNP20009.
Due to the role of chemotaxis in bacterial tumor colonization and eradication remaining unclear, we aimed to compare VNP20009 and VNP20009 cheY+ primary tumor colonization and impact on metastasis in an aggressive 4T1 mouse mammary carcinoma model. Bacterial tumor colonization and metastatic potential of the cancerous cells to the lungs appear bacterial chemotaxis independent. Moreover, mice bearing tumors exposed to Salmonella exhibited increased morbidity that was associated with significant liver disease. Our results suggest that in our timeline VNP20009 may not be safe or efficacious when used in the context of immunocompetent animals with aggressive, metastatic breast cancer. In a novel approach, we aimed to understand the bacterial-cancer cell relationship within the tumor microenvironment, with an emphasis on gene expression changes occurring within the eukaryotic transcriptome. We employed the B16-F10 mouse melanoma model because VNP20009 is known to colonize and eradicate these tumors in mice. First, we optimized a timeline for Salmonella treatment of mouse melanoma, finding a dramatic delay in tumor growth between 2 and 7 days due to the presence of Salmonella. Additionally, we observed upregulation of the IFN-gamma signaling pathway within tumor tissue upon exposure to Salmonella after 7 days. In future studies, we aim to analyze the bacterial transcriptome in the tumor microenvironment to gain unique understanding and contribute to knowledge supporting bacterial-mediated cancer therapies.Ph. D.
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Liu, Ping. "Structural, Kinetic and Mutational Analysis of Two Bacterial Carboxylesterases." Digital Archive @ GSU, 2007. http://digitalarchive.gsu.edu/biology_diss/26.
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The crystal structures of two thermostable carboxylesterase Est30 and Est55 from Geobacillus stearothermophilus were determined to help understand their functions and applications in industry or medicine. The crystal structure of Est30 was determined at 1.63 Å resolution by the multiple anomalous dispersion method. The two-domain Est30 structure showed a large domain with a modified alpha/beta hydrolase core including a seven, rather than an eight-stranded beta sheet, and a smaller cap domain comprising three alpha helices. A 100 Da tetrahedral ligand, propyl acetate, was observed to be covalently bound to the side chain of Ser94 in the catalytic triad. This ligand complex represents the first tetrahedral intermediate in the reaction mechanism. Therefore, this Est30 crystal structure will help understand the mode of action of all enzymes in the serine hydrolase superfamily. Est55 is a bacterial homologue of the mammalian carboxylesterases involved in hydrolysis and detoxification of numerous peptides and drugs and in prodrug activation. Est55 crystals were grown at pH 6.2 and pH 6.8 and the structures were determined at resolutions of 2.0 and 1.58 Å respectively. Est55 folds into three domains, a catalytic domain, an α/β domain and a regulatory domain. This structure is in an inactive form; the side chain of His409, one of the catalytic triad residues, is pointing away from the active site. Moreover, the adjacent Cys408 is triply oxidized and lies in the oxyanion hole, which would block the entry of substrate to its binding site. This structure suggested a self-inactivation mechanism, however, Cys408 is not essential for enzyme activity. Mutation of Cys408 showed that hydrophobic side chains at this position were favorable, while polar serine was unfavorable for enzyme activity. Both Est30 and Est55 were shown to hydrolyze the prodrug CPT-11 into the active form SN-38. Therefore, Est30 and Est55 are potential candidates for use with irinotecan in cancer therapy. The catalytic efficiency (kcat/Km) of Est30 is about 10-fold lower than that of Est55. The effects of the Cys408 substitutions on Est55 activity differed for the two substrates, p-NP butyrate and CPT-11. Mutant C408V may provide a more stable form of Est55.
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Almeida, Joana Raquel Santos Leite. "Multidrug resistant bacteria inactivation by photodynamic therapy." Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/7295.
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Mestrado em Biologia Aplicada - Microbiologia Clínica e AmbientalThe development of antimicrobials promoted the idea that diseases provoked by microorganisms would diminish and would be reduced to the insignificancy to human health. However, the great amount of antibiotics used in human medicine and veterinary lead to a selection of pathogenic bacteria resistant to multiple antibiotics, being hospital wastewaters one of the most important sources of antibiotic-resistant organisms and antibiotic-resistance genes that are released into the environment. The significant increase in the development of multiple resistance mechanisms to antibiotics caused an increase in the research of alternative treatments that may be cost effective and human friendly. Antimicrobial photodynamic therapy (aPDT) is a quickly expanding technology for the treatment of diseases since it inactivates efficiently microorganisms, is cost effective and human safe. The general objective of this work was to assess the inactivation of 4 clinical multidrug-resistant bacteria by aPDT, using a tetracationic porphyrin (PS). The efficacy of aPDT was assessed in phosphate buffered saline (PBS) and in hospital residual water for each isolated bacterium and for the bacteria mixtured all together. The synergistic effect of aPDT and antibiotics (ampicillin and chloramphenicol) was also evaluated as well as the effect of sodium dodecylsulphate (SDS) on aPDT efficiency. The results show an efficient inactivation of multidrug-resistant bacteria in PBS using 5 μM of PS during 270 minutes in the presence of a light fluence rate of 40 W.m-2 (reduction of 6 to 8 log). In the residual water, the inactivation of the 4 bacteria was also efficient and the decrease in bacterial number starts even sooner. It was observed a faster decrease in bacterial number when aPDT was combined with the addition of ampicillin and chloramphenicol at concentrations of 16 and 32 μg mL-1 (MIC dose 32 μg mL-1 for both antibiotics). The efficiency of aPDT with a lower porphyrin concentration (2.5 μM) in the presence of antibiotics at MIC dose was not significantly different of that obtained when just the PS was used. The addition of SDS did not affect the efficiency of aPDT. The results of this study showed that aPDT inactivate efficiently multidrug-resistant bacteria, in hospital residual water the bacterial inactivation is faster than in PBS, the combination of antibiotics and aPDT acts more efficiently than the aPDT alone, but aPDT in the presence of SDS does not affect the efficiency of bacterial inactivation. In conclusion, aPDT is effective to combating microbial diseases transmitted by multidrug-resistant bacteria and can be used to increase the efficacy of classical antibiotics.
O desenvolvimento de agentes antimicrobianos levou a pensar que as doenças provocadas por microrganismos diminuiriam, tornando-se insignificantes para a saúde humana. No entanto, a grande quantidade de antibióticos utilizados na medicina humana e veterinária levaram a uma selecção de bactérias patogénicas resistentes a muitos antibióticos, sendo os efluentes hospitalares uma das fontes mais importantes de organismos resistentes a antibióticos e de genes de resistência a antibióticos que são lançados no meio ambiente. O aumento significativo no desenvolvimento de diversos mecanismos de resistência a antibióticos provocou um aumento na pesquisa de tratamentos alternativos que apresentem baixo custo e que não apresentem efeitos adversos para o homem. A terapia fotodinâmica antimicrobiana (aPDT) alternativa aos antibióticos para o tratamento de doenças, visto que inactiva eficientemente microrganismos, é barata e segura. O objectivo geral deste trabalho foi avaliar a inactivação de quatro isolados clínicos de bactérias multirresistentes pela aPDT, utilizando uma porfirina tetracatiónica (PS). A eficácia da aPDT foi avaliada em solução tampão (PBS) e em águas residuais hospitalares para cada bactéria isolada e para a mistura das 4 bactérias juntas. O efeito sinergético da aPDT e antibióticos (ampicilina e cloranfenicol) também foi avaliado, assim como o efeito do dodecilsulfato de sódio (SDS) sobre a eficiência da aPDT. Os resultados mostram uma inactivação eficiente de bactérias multirresistentes em PBS utilizando 5 μM de PS, durante 270 minutos na presença de 40 W.m-2 de luz (redução de 6-8 log). Na água residual hospitalar, a inactivação das 4 bactérias foi igualmente eficiente, começado mesmo a diminuição do número de bactérias mais cedo que em PBS. Foi observado uma redução mais acentuada no número de bactérias quando a aPDT foi combinada com a adição de ampicilina e cloranfenicol nas concentrações de 16 e 32 μg mL-1 (dose MIC de 32 μg mL-1 para ambos os antibióticos). A eficiência da aPDT com uma concentração inferior de PS (2.5 μM) na presença de antibióticos na dose MIC não foi significativamente diferente da obtida quando foi utilizado apenas a porfirina. A adição do SDS também não afectou a eficiência da aPDT. Os resultados deste estudo mostraram que a aPDT inactiva bactérias multirresistentes de forma eficiente; em água de esgoto hospitalar a inactivação bacteriana é mais rápida do que em PBS, a combinação de antibióticos e aPDT actua de forma mais eficiente do que a APDT sozinha, mas eficiência da aPDT na presença de SDS não é afectada. Em conclusão, aPDT é eficaz para combater doenças microbianas transmitidas por bactérias multi-resistentes e podem ser usados para aumentar a eficácia dos antibióticos clássicos.
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Coston, Amber Dawn. "Cancer vaccine and therapy." Connect to resource, 2006. http://hdl.handle.net/1811/6557.
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Thesis (Honors)--Ohio State University, 2006.Title from first page of PDF file. Document formatted into pages: contains 23 p.; also includes graphics. Includes bibliographical references (p. 21-23). Available online via Ohio State University's Knowledge Bank.
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Zeicher, Marc. "Oncolytic viruses cancer therapy." Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210439.
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Wild-type viruses with intrinsic oncolytic capacity in human includes DNA viruses like some autonomous parvoviruses and many RNA viruses. Recent advances in molecular biology have allowed the design of several genetically modified viruses, such as adenovirus and herpes simplex virus that specifically replicate in, and kill tumor cells. However, still several hurdles regarding clinical limitations and safety issues should be overcome before this mode of therapy can become of clinical relevance. It includes limited virus spread in tumor masses, stability of virus in the blood, trapping within the liver sinusoids, transendothelial transfer, and/or vector diffusion of viral particles to tumor cells, limited tumor transduction, immune-mediated inactivation or destruction of the virus. For replication-competent vectors without approved antiviral agents, suicide genes might be used as fail-safe mechanism. Cancer stem cells are a minor population of tumor cells that possess the stem cell property of self-renewal. Therefore, viruses that target the defective self-renewal pathways in cancer cells might lead to improved outcomes.In this thesis, data we generated in the field of oncolytic autonomous parvoviruses are presented.
We replaced capsid genes by reporter genes and assessed expression in different types of human cancer cells and their normal counterparts, either at the level of whole cell population, (CAT ELISA) or at the single cell level, (FACS analysis of Green Fluorescent Protein). Cat expression was substantial (up to 10000 times background) in all infected tumor cells, despite variations according to the cell types. In contrast, no gene expression was detected in similarly infected normal cells, (with the exception of an expression slightly above background in fibroblasts.). FACS analysis of GFP expression revealed that most tumor cells expressed high level of GFP while no GFP positive normal cells could be detected with the exception of very few (less than 0.1%) human fibroblast cells expressing high level of GFP. We also replace capsid genes by genes coding for the costimulatory molecules B7-1 and B7-2 and show that, upon infection with B7 recombinant virions, only tumor cells display the costimulatory molecules and their immunogenicity was increased without any effect on normal cells. Using a recombinant MVM containig the Herpes Simplex thymidine kinase gene, we could get efficient killing of most tumor cell types in the presence of ganciclovir, whithout affecting normal proliferating cells. We also produced tetracycline inducible packaging cell lines in order to improve recombinant vectors yields. The prospects and limitations of these different strategies will be discussed.
An overview is given of the general mechanisms and genetic modifications by which oncolytic viruses achieve tumor cell-specific replication and antitumor efficacy. However, as their therapeutic efficacy in clinical trials is still not optimal, strategies are evaluated that could further enhance the oncolytic potential of conditionally replicating viruses in conjunction with other standard therapies.
Another exciting new area of research has been the harnessing of naturally tumor-homing cells as carrier cells to deliver oncolytic viruses to tumors. The trafficking of these tumor-homing cells (stem cells, immune cells and cancer cells), which support proliferation of the viruses, is mediated by specific chemokines and cell adhesion molecules and we are just beginning to understand the roles of these molecules. Finally, we will explore some ways deserving further study in order to be able to utilize various oncolytic viruses for effective cancer treatment.
Doctorat en sciences, Spécialisation biologie moléculaire
info:eu-repo/semantics/nonPublished
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Edinger, Daniel. "siRNA therapy for cancer." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-158123.
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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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Pendsé, D. A. "Photodynamic therapy and focal therapy for prostate cancer." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1353787/.
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Prostate Cancer is the most commonly diagnosed cancer in men. The incidence of prostate cancer has risen over the last two decades, although mortality rates have not increased to the same extent. For many men with localised prostate cancer the choice of treatment lies between radical surgery or radiotherapy and active surveillance. Evidence suggests that the survival benefits related to radical treatment are small, and that conservative management may be appropriate for many men. A strategy of focal therapy in prostate cancer aims to treat tumour foci within the prostate, without treating the whole gland, with a resultant reduction in side-effects. Photodynamic therapy (PDT) is the use of a photosensitising drug, which when activated by light can cause cellular damage. Tookad is a new-generation photosensitiser, which is activated in vasculature. Phase I and II clinical trials of Tookad PDT in men with recurrent prostate cancer following radiotherapy have been performed. These studies show that it is possible to ablate prostate tissue with Tookad PDT. This thesis describes a phase I/II clinical trial evaluating the safety and efficacy of Tookad PDT in men with primary prostate cancer. Treatments were performed under general anaesthetic, using 2mg/kg Tookad and interstitial light delivery via cylindrical diffuser fibres. 15 patients were included in part A (single-fibre, light-dose-escalation), 19 patients in part-B (multi-fibre, focal and whole-gland ablation). Follow-up was for 12-months, with assessment of treatment effect made on MRI. Post-treatment imaging demonstrated that prostate tissue can be ablated in a reproducible and controlled manner with Tookad PDT. Although genitourinary side-effects were relatively few, significant cardiovascular complications in this study lead to early termination of the clinical trial and withdrawal of the drug. Results suggest that Tookad PDT could potentially deliver either focal or whole-gland therapy. Further studies with modified photosensitsers are underway.
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Harris, Jonathan David. "Targeted gene therapy for cancer." Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309239.
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Marani, Michela. "Targeting apoptosis for cancer therapy." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404985.
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Rigg, Anne Sagar. "Gene therapy for human cancer." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341902.
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Pandha, Hardev Singh. "Gene transfer therapy for cancer." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299872.
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Roberts, Fiona L. "Cancer therapy : origin and application." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=16930.
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In this thesis we use mathematical techniques to model two biological systems. First, we examine the growth dynamics of the antibiotic producing bacteria Streptomyces coelicolor and present a system of PDEs. We study the system both numerically and analytically. Due to oscillations in the numerical solution when solved using NAG, which uses a finite difference discretization, we change to a finite element discretization which corrects the oscillations. S. coelicolor also produces anticancer drugs, these can be encapsulated during the self-assembly of nanometre-sized vesicles, BPVs (biomimetic polymer vesicles) which are used as a novel targeted cancer therapy. We present a system of ODEs that focuses on the binding kinetics between cell-surface receptors and targeting molecules (ligands) on the BPV. We solve the system numerically, showing there is an optimal number of ligands per BPV for optimal uptake by tumour cells. We extend the model to allow for the infiltration of BPVs into tumour spheroids. Numerical solutions show that the growth of the spheroid is linear if the therapeutic BPVs are absent, and slows in the other case (for some parameter values). Using large time asymptotics we explore regions of parameter space where either steady states or travelling waves will occur.
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Marshall, Ann. "Catalytic antibodies for cancer therapy." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299626.
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Barr, Hugh. "Photodynamic therapy for colorectal cancer." Thesis, University of Liverpool, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329398.
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Roeder, Geraldine Elizabeth. "Gene therapy for cervical cancer." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268704.
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Liu, David Victor. "Protein engineering for cancer therapy." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/73796.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2012.Cataloged from PDF version of thesis.
Includes bibliographical references.
The immunosuppressive effects of CD4⁺CD25⁺ regulatory T cells (Tregs) interfere with anti-tumor immune responses in cancer patients. In the first part of this work, we present a novel class of engineered Interleukin-2 (IL-2) analogues that antagonize the IL-2 receptor, for inhibiting Treg suppression. These antagonists are engineered for high affinity to the IL-2 receptor a subunit and low affinity to either the [beta] or [gamma] subunit, resulting in a signaling-deficient IL-2 analogue that sequesters the IL-2 receptor a subunit from wild type IL-2. Using this design, human and mouse IL-2 antagonists were generated with inhibition constants ranging from 200 pM to 5 nM in vitro. Genetic fusions with IgG2a Fc enhanced serum half-life up to 30 hours. In order to study the effects of IL-2 antagonism, Fc fragments with disrupted effector functions were used. Fc-antagonist fusions bound to but could not deplete peripheral Tregs. They downregulated CD25 on Tregs, but could not perturb Treg function in a syngenic tumor model, presumably due to the high sensitivity of the IL-2 receptor and a high threshold for antagonism in vivo. In the second part of this work, we present a novel multi-agent protein-based system for targeted siRNA delivery that provides potential advantages over other nanoparticle- and proteinbased delivery vehicles. In the first agent, the double stranded RNA binding domain (dsRBD) of human protein kinase R is used as an siRNA carrier, in fusion proteins that target epidermal growth factor receptor (EGFR). Targeted dsRBD proteins deliver large amounts of siRNA to endosomal compartments in an EGFR expressing cell line, but efficient gene silencing is limited by endosomal escape. The use of a second agent that contains the cholesterol dependent cytolysin, perfringolysin 0, enhances endosomal escape of siRNA. Targeted delivery of perfringolysin 0 induces gene silencing in a dose-dependent and EGFR-dependent manner. However, cytotoxicity of the cytolysin creates a narrow therapeutic window. Multiepitopic EGFR binders that induce EGFR clustering are explored as tools for enhancing gene silencing efficiency. Interestingly, they not only enhance gene silencing potency but also protect against toxicity from EGFR-targeted cytolysins, thus significantly widening the therapeutic window of this method.
by David Victor Liu.
Ph.D.
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Yeung, Yik Andy. "Antibody engineering for cancer therapy." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/32325.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005.Vita.
Includes bibliographical references (leaves 131-141).
Antibodies targeting various tumor-associated antigens have been developed successfully to treat cancer. In this Thesis, novel antibodies and antibody-conjugate against two tumor antigens, AF-20 antigen and human aspartyl (asparaginyl) [beta]- hydroxylase (HAAH), were developed. Previously, these two tumor antigens have been shown to be present on a variety of tumor cells, while they have minimal expression on normal tissues, rendering them excellent targets for antibody therapy. For the AF-20 work, the variable region (V) gene of a previously isolated mouse monoclonal antibody (mAb) AF-20 was cloned from hybridoma mRNA and used to construct an AF-20 single-chain Fv (scFv). The AF-20 scFv was shown to bind specifically to the same epitope as mAb AF-20 with a binding affinity of 4nM. The AF- 20 scFv was also internalized into tumor cells in a manner identical to that of the original mAb AF-20. The scFv was later employed for cellular internalization of virus-sized fluorescent quantum dots. In addition, to demonstrate the versatility of this antibody, an immunotoxin composed of AF-20 scFv fused to the highly cytotoxic recombinant toxin gelonin was constructed, and its in-vitro efficacy against three different tumor cell lines were evaluated. The IC50 of the AF-20 scFv-gelonin fusion was consistently one to two logs lower than the IC50 of free gelonin on FOCUS (liver), L3.6pl (pancreas) and PC3 (prostate) cells, further demonstrating the capability of the AF-20 scFv as a targeting module. Therefore, this AF-20 scFv is a potential internalization vector for toxins, enzymes, radionuclides and virus for targeted therapy of AF-20-antigen expressing tumor cells.
For the HAAH study, twelve novel human scFv against HAAH were isolated from a human non-immune scFv library displayed on the surface of yeast. Five of the twelve scFv were reformatted as human IgG 1. One of the reformatted IgG, 6-22, showed significant binding to recombinant HAAH protein in ELISA, tumor cell lines, and tumor tissues. 6-22 IgG was also shown to target the catalytic domain of HAAH, and its apparent dissociation constant was determined to be 1.OnM. 6-22 IgG alone does not exhibit significant cytotoxicity toward the tumor cells. However, 6-22 IgG internalizes into tumor cells and can therefore be employed to deliver cytotoxic moieties into tumor cells. A goat anti-human IgG-saporin conjugate was delivered into tumor cells by 6-22 IgG and hence elicited cytotoxicity toward the tumor cells in vitro. Meanwhile, the monovalent affinity of 6-22 scFv was too low for therapeutic or diagnostic application, so 6-22 scFv was affinity matured using directed evolution and yeast surface display. After two rounds of mutagenesis, a mutant, C4-18, with an affinity of 0.6nM was isolated. Overall, these human [gamma]-HAAH scFv and IgG can potentially be used in the diagnosis and therapeutic treatment of HAAH-expressing tumor cells.
by Yik Andy Yeung.
Ph.D.
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Park, Joshua Inshik. "Matrix attachment therapy for cancer." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. 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:3311355.
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Flores, Glen P. "Ferroelectric hyperthermia for cancer therapy." [Gainesville, Fla.] : University of Florida, 2003. http://purl.fcla.edu/fcla/etd/UFE0001113.
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Abdallah, Banu. "Carbon nanotubes in cancer therapy." Thesis, University of Central Lancashire, 2013. http://clok.uclan.ac.uk/9658/.
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Carbon Nanotubes (CNTs) are highly attractive vehicles for the delivery of bio-molecules into living systems specifically for applications in cancer therapy. Two main types of CNTs; single-walled (SWNT) and multi-walled (MWNT) have been investigated. Pristine CNTs are poorly soluble in aqueous solvents, and therefore need to be functionalized (f-CNT) to enhance their solubility and biocompatibility. The f-CNTs possess the ability to cross cell membranes and enter cells consequently having the potential as vehicles for drug delivery. Polyethylene glycol (PEG400) and Pluronic®F127 (PF127) functionalized SWNTs and MWNTs have been investigated in this study for in vitro cancer therapy. Both have demonstrated high tumour suppression efficacy with respect to an anti-cancer drug Paclitaxel, when utilised solely. However, f-CNTs for the delivery of anti-cancer agents for brain tumours, in particular the most common tumour Glioblastoma, have not been researched. The toxicity of these materials is another issue that requires further investigation. Cytotoxicity of CNTs is thought to be dependent on several characteristics such as length, purity and type of functionalization. The aim of this study was to characterize, functionalize and investigate in vitro cell cytotoxicity of f-CNTs with and without Paclitaxel (PTX). As dispersing and stabilization agents two polymeric systems were used; PEG400 and PF127. CNTs characteristics have been investigated by using various techniques and two stabilization and dispersing agents have been used for functionalization. Raman spectra have been recorded using two laser lines at 325 nm and 488 nm. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) were used to analyse their structure and morphology. All samples were functionalized, homogenised, centrifuged and their ζ-potentials were measured. CNTs were found to be in a size range of 100 nm to several microns long, with diameter values ranging from 07 ± 1.0 nm for SWNT and inner diameter I.D. 10-20 nm and 30-40 nm Outer Diameter values (O.D.) with 6-12 concentric walls for MWNT. Both SWNT and MWNT exhibited stability in both polymeric systems implemented even after a 10 day period. Particularly PEG400 based formulations showed superior performance in terms of greater ζ-potential values. Notable shifts in G-band were examined confirming the presence of f-CNTs. Higher entrapment efficiency was accomplished with f-CNTs reaching a maximum efficiency at 200 μg/ml. Cell lines SVGp12 and U87-MG were exploited for cytotoxicity evaluations. SWNT and MWNT demonstrated insignificant cytotoxic effects on SVGp12 (normal astrocytes) cell lines even at elevated concentrations of up to 15 mg/ml. Nevertheless, f-CNTs showed significant reduction in the cell viability at low Paclitaxel concentrations on U87-MG grade IV Glioblastoma. As a selection of CNTs have been investigated by various researchers, it is exceptionally challenging to conclusively state whether or not they are indeed toxic. This research into CNTs has successfully examined the effects of co-formulation with various components and the potential effects on drug delivery for cancer cells. Conceptually, CNTs are rightfully labelled as the king of nanomaterials due to their elusive chemical and physical properties; ensure that they are likely to receive much attention in the not too distant future.
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Montel, de la Roche Noelia <1990>. "Innovative approaches to cancer therapy." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amsdottorato.unibo.it/9369/1/Noelia_thesis.pdf.
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Cancer is a term used to describe complex diseases characterized by abnormal cell-proliferation with different factors to take into consideration, reason for which nowadays there are many types of treatments with limited success. Therefore, innovative anticancer agents are required.
Recently, anticancer research has been focused on epigenetics. Among epigenetic actors, Chromodomain (ChD)-containing proteins have gained ever-increased interest. These proteins, whose altered expression or mutations in cancer lead to abnormal gene transcription, are involved in epigenetic regulation of transcription by recognizing methylated lysine residues on histones.
According to this information, in the first part of this thesis, an innovative epigenetic approach was applied to design and synthetize small-molecules as potential ChDs binders for cancer treatment. In detail, we reported the identification of two hit compounds (2 and 3) and the further structure-activity relationship studies. A fluorescence polarization competition assay was employed to evaluate the obtained derivatives.
Cancer research activities have also taken advantage of innovation in emerging technologies. As an example, technical advances have allowed to apply X-ray crystallography in a high-throughput way for compound screening. Therefore, in the second part of this work a fragment-based drug discovery approach based on high-throughput X-ray crystallography was applied, in collaboration with Paul Scherrer Institute, for identifying new binders of tubulin. In this context, compound 29 was identified as a binder of tubulin Colchicine-site, previously validated for cancer treatment. Structural similarity of this compound with Nocodazole, an antineoplastic agent co-crystallized with tubulin at the same Colchicine-site, and the capability of both molecules to bind the same tubulin pocket, encouraged us to develop two series of 29 analogs by combining synthetic efforts with computer-aided drug design protocols.
For some synthetized derivatives, X-ray crystallography and Resazurin assay were employed to evaluate the binding ability at the tubulin Colchicine-site and the capacity to affect cell viability, respectively.
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Andele, Kossivi Jean D'Arc Pacome <1994>. "BIOINSPIRED NANODRUGS FOR CANCER THERAPY." Master's Degree Thesis, Università Ca' Foscari Venezia, 2020. http://hdl.handle.net/10579/17760.
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Cancer is a complex disease that can start mainly in any organ in the body when abnormal cells grow in an uncontrolled manner to invade neighbouring parts of the body to spread to other organs.The inhibition of proteins that control multiple oncogenic pathways could be a solution to treat cancer. One protein involved in multiple cellular pathways is peptidylprolyl PIN1 an isomerase formed by a WW domain and a catalytic domain with a molecular weight of 18 KDa. To identify molecules that are capable to inhibit in vivo PIN1, our laboratory collaborator used consensus docking to model existing PIN1‐ligand X‐ray structures and screened a chemical database for candidate inhibitors. This effective technique allowed identifying new hit compounds, thanks to receptor based on pharmacophore screening strategies which are commonly developed and applied on different classes of protein targets. Docking technique is used for in silico identification of novel hit compounds. Due to problem related to drug loading efficiency, in this study a compound C17 was obtained through docking, modified with pluronic acid and coated with albumin in order to increase the uptake of the drug. This formulation was used in order to increase the circulation half-life, since albumin can bind to the hydrophobic moieties of the C17 in order to prevent opsonization and phagocytosis. In the other side being albumin highly demanding source of energy of tumors, it has been used to improve the uptake of the drug by cancer cell lines.
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Jones, Mitchell. "Enzymatically active probiotic bacteria for topical and oral therapy." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103498.
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A novel approach whereby one can use probiotic bacteria for the purpose of topical and oral therapy is presented. More specifically, a treatment modality using enzymatically active probiotic production of gaseous nitric oxide (gNO) for wound healing, antimicrobial, cosmetic, and dermatologic therapy is presented. In another aspect, a probiotic treatment modality for metabolic disease and metabolic syndrome using nitrate reductase (NiR) active probiotic bacteria is explored. In concurrence to these requirements, several in-vitro methods are designed and discussed in this report. For some of these studies the use of alginate microcapsules is explored. Results show that probiotic patches can be used for the production of gNO above therapeutic levels and for therapeutic durations and that probiotic gNO-producing patches are highly bacteriostatic, bactericidal, and fungicidal. Results show that the novel gNO-producing probiotic patch can be used to improve wound healing and increase the likelihood of wound closure in ischemic and infected full-thickness dermal wounds in a New Zealand White Rabbit model and that daily application of the patch is safe with respect to body weight, blood morphology, haematology, blood biochemistry, and methemoglobin levels. Also, results show that novel NiR-active probiotic bacteria can be selected for nitrate reductase (NiR) activity in-vitro, and can be microencapsulated or delivered free under simulated GI conditions, and in the presence of various food matrices while maintaining NiR activity, confirming the lab scale feasibility of the approach in delivering the probiotic orally for treating hypertension, inflammatory bowel disease, gastric ulcers, diabetes and thrombosis. These findings may provide effective, safe, and less costly alternatives for delivering gNO topical and oral for therapy.Une nouvelle approche selon laquelle on peut utiliser des bactéries probiotiques dans le but de la thérapie topique et de la thérapie par voie orale est présentée. Plus précisément, une modalité de traitement, utilisant des probiotiques à activité enzymatique produisant de l'oxyde nitrique gazeux (NOg) pour la cicatrisation des plaies, ainsi que comme thérapies antimicrobiennes, cosmétiques et dermatologiques, est présenté. Dans un autre aspect, une modalité de traitements probiotiques pour les maladies métaboliques et les syndromes métaboliques en utilisant du nitrate réductase (NiR) bactéries probiotiques actives est explorée. En accord à ces exigences, plusieurs méthodes in vitro sont conçus et discutés dans le présent rapport. Pour certaines de ces études l'utilisation de micro capsules d'alginate est explorée également. Les résultats montrent que les correctifs probiotiques peuvent être utilisés pour la production de NOg au-dessus des niveaux thérapeutiques et pour des durées thérapeutiques et que les patches de NOg-producteurs de probiotiques sont très bactériostatiques, bactéricide et fongicide. Les résultats montrent que les nouvelles patches de NOg producteurs de probiotiques peuvent être utilisés pour améliorer la cicatrisation et augmenter la probabilité de fermeture de la plaie dans les plaies de pleine épaisseur ischémique et infectés par voie cutanée dans un modèle néo-zélandais White Rabbit et que l'application quotidienne des patches est sécuritaire en proportion avec le poids du corps, la morphologie du sang, l'hématologie, biochimie sanguine, et les niveaux de méthémoglobine. En outre, les résultats montrent que les nouvelles NiR-bactéries probiotiques actives peuvent être sélectionnés pour la nitrate réductase (NiR) l'activité in vitro, et peut être micro encapsulées ou remis gratuitement dans des conditions simulées GI, et en présence de diverses matrices alimentaires, tout en maintenant l'activité NiR, confirmant ainsi la faisabilité échelle du laboratoire de l'approche dans la réalisation des probiotiques par voie orale pour le traitement de l'hypertension, les maladies inflammatoires de l'intestin, les ulcères gastriques, le diabète et la thrombose. Ces résultats peuvent s'avérer efficaces, sûrs, et des solutions moins coûteuses pour offrir NOg topiques et oraux pour le traitement.
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Hillinger, Sven. "Immune targeted therapy for lung cancer /." Zürich, 2006. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253405.
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Yang, Ya-Ting. "Molecularly targeted therapy for ovarian cancer." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1149015359.
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Culp, W. David. "Identifying molecular targets for cancer therapy /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-188-3/.
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Lin, Chen-ju. "Targeting translation initiation for cancer therapy." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96981.
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The recruitment of ribosomes to the 5' end of mRNAs in eukaryotic cells is generally thought to be the rate-limiting step of translation initiation and this process is mediated by the eukaryotic initiation factor 4F complex (eIF4F). This complex consists of three subunits: eIF4E, a mRNA-cap binding protein, eIF4A, a RNA helicase and eIF4G, a large molecular scaffold that mediates the binding of mRNA to ribosomes. Deregulation of translation initiation through eIF4F activation has been widely observed in human cancers. The eIF4F complex lies downstream of key signalling pathways involved in oncogenesis (such as c-Myc and PI3K/Akt/mTOR), thus targeting translation initiation provides an attractive therapeutic approach for cancer therapy. Here, we show that c-Myc stimulates protein synthesis by up-regulating the expression and activity of not only eIF4E, but that of the other two subunits of eIF4F. In turn, this elevated eIF4F levels result in increased synthesis and function of c-Myc, establishing a positive feedforward loop. We used the Eμ-myc lymphoma mouse model to show that expression of the three eIF4F subunits is also up-regulated by c-Myc in vivo. Most importantly, we demonstrate that loss of eIF4E function using inducible and reversible RNA interference (RNAi) greatly delays the rates of c-Myc-induced lymphoma development. These data suggest that targeting eIF4E in vivo is an effective therapeutic approach. Since the assembly of eIF4F complex is regulated by mTOR signaling, the coupling of c-Myc to eIF4F is under mTOR control. In the course of a screen of inhibitors of the PI3K/Akt/mTOR signalling pathway, we found two small molecules, silibinin and the anti-depressant sertraline, both of which show anti-proliferative effects on breast cancer cells. Silibinin and sertraline effectively target eIF4F complex function by downregulating mTOR signaling. Importantly, sertraline is able to enhance the chemosensitivity of PTEN (+/-)/Eμ-Myc lymphomas to the chemotherapeutic agent doxorubicin in vivo. Thus, targeting mTOR-dependent translation initiation shows anti-cancer activity in this pre-clinical setting.Il est généralement admis que le recrutement des ribosomes à l'extrémité 5' des ARN messagers (ARNm) est l'étape limitante de l'initiation de la traduction chez les eucaryotes. Cette étape est dépendante de l'activité du complexe d'initiation eIF4F qui comprend trois sous-unités: eIF4E, une protéine liant la coiffe des ARNm, eIF4A, une hélicase d'ARN et eIF4G, une grande protéine d'échafaudage dont le rôle est de coordonner la liaison du ribosome à l'ARNm. Le dérèglement du contrôle de l'initiation de la traduction suite à l'activation d'eIF4F est observé fréquemment chez les cancers humains. L'activité de ce complexe est contrôlée par plusieurs voies de signalisation clés qui sont impliquées dans la formation des tumeurs (tels que c-Myc et PI3K/Akt/mTOR). Donc, cibler l'initiation de la traduction représente une avenue attrayante pour contrer le cancer. Nous démontrons ici que l'oncogène c-Myc peut stimuler la synthèse protéique en favorisant l'expression et l'activité de non-seulement eIF4E, mais aussi des deux autres sous-unités du complexe eIF4F. En réponse à cela, les niveaux supérieurs d'eIF4F permettent une augmentation de la synthèse et donc de l'activité de c-MYC, établissant alors une boucle auto-stimulante. Nous avons utilisé le modèle de souris Eμ-myc pour démontrer que l'expression de chacune des sous-unités d'eIF4F est stimulée par c-Myc in vivo. Plus important encore, nous avons démontré que la réduction des niveaux d'eIF4E en utilisant la technique d'interférence à ARN (ARNi) de manière inductible et réversible freine considérablement le développement de lymphomes par c-Myc. Ces données suggèrent que cibler eIF4E in vivo est une approche thérapeutique viable et efficace. De plus, puisque l'assemblage d'eIF4E est contrôlé de mTOR, il en résulte donc que le couplage de c-Myc et d'eIF4F est donc aussi sous contrôle de cette voie de signalisation. Suite à un cribblage de molécules inhibitrices de la voie PI3K/Akt/mTOR, nous avons identifié deux molécules, la silibinine et l'anti-dépresseur sertraline, qui ont la propriété de bloquer la prolifération de cellules du cancer du sein. La silibinin et la sertraline inhibent efficacement l'activité du complexe eIF4F en ciblant la voie de signalisation de mTOR. Par surcroît, la sertraline accentue fortement la sensibilité des lymphomes PTEN (+/-)/Eμ-Myc à l'agent chimiothérapeutique doxorubicin in vivo. En conclusion, il appert que cibler le contrôle de la traduction par mTOR peut contrer efficacement le cancer dans ce modèle de cancer préclinique.
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Samani, Amir Abbas. "IGF-IR targeted cancer gene therapy." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18206.
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Since the declaration of “War on cancer” in 1971, and with the insight provided by recent advances in human genetics and in molecular technology , the field of cancer biology has been expanded rapidly providing hope that a cure for this lethal disease will be found. One of the major contributions of the field of cell biology to the understanding of malignant diseases has been the identification of growth factors and their receptors as major promoters of transformation and malignant progression. In particular, the appreciation of the central role that receptor tyrosine kinases (RTK) play in different cancers has led to development of effective therapeutic reagents. One of the RTK implicated in malignant progression is the receptor for the type 1 insulin like growth factor (IGF-IR) that has been identified as a target for anti-cancer treatments. Cancer gene therapy is a rapidly developing modality for cancer therapy. Many gene therapy strategies have been developed generally targeting the genes and proteins involved in cancer initiation and progression. To design a successful gene therapy strategy requires an understanding of the molecular basis of cancer progression and knowledge of human and animal genetics and physiology. In the present work, I have introduced two different strategies to inhibit liver metastases formation using established human and murine cancer cell lines. The first strategy is based on targeting the IGF-IR in tumor cells using an antisense technology (chapter 2). This strategy was also shown to be applicable in cancer gene therapy of glioblastoma growing in the brain (chapter 3). Very interestingly and for the first time, we showed that reduction of IGF-IR expression levels in glioma cells can induce a state of dormancy, providing a unique model to study this clinically important phenomenon. As the second strategy, I designed a novel soluble IGF-IR molecule. I showed that expression of this molecule in tumor cells caused an inhibitioDepuis la “déclaration de la guerre contre le cancer” en 1971 et grâce aux avancées en génétique humaine et technologie moléculaire, le domaine de la biologie du cancer s’est rapidement étendu, fournissant l’espoir qu’un traitement pour cette maladie léthale sera trouvé. Une des contributions majeures du domaine de la biologie cellulaire pour la compréhension des maladies malignes a été la mise en évidence du rôle des facteurs de croissance et de leurs récepteurs dans la transformation et la progression maligne. En particulier, le rôle central que jouent les récepteurs à tyrosine kinase (RTK) dans différents cancers a abouti au développement d’agents thérapeutiques efficaces. Un des RTK impliqué dans la progression maligne est IGF-IR, le récepteur de type 1 du facteur de croissance de l’insuline qui a été identifié comme étant une cible pour des traitements anti-cancéreux. La thérapie génique est en pleine voie de développement pour la thérapie du cancer. De manière générale, de nombreuses stratégies de thérapie ont été développées en ciblant les gènes et protéines impliqués dans l’initiation et la progression du cancer. L’élaboration d’une stratégie de thérapie génique efficace nécessite la compréhension des bases moléculaires de la progression du cancer ainsi que la connaissance de la génétique et la physiologie humaine et animale Dans ce travail, j’ai introduis deux stratégies différentes pour inhiber la formation de métastases du foie en utilisant des lignées cellulaires cancéreuses humaines et murines. La première stratégie est basée sur le ciblage de IGF-IR dans des cellules tumorales en utilisant une stratégie antisens (chapitre 2). Cette stratégie s’est également avérée être appliquable à la thérapie génique du cancer de glioblastome dans le cerveau (chapitre 3). De facon intéressante et ce, pour la première fois, nous avons montré que la diminution de l’exp
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Linardou, Helen. "Targeting deoxyribonuclease-I for cancer therapy." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286371.
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Lau, Kelvin Kar Wing. "Vascular targeting of anti-cancer therapy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311869.
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Ahmed, Sarah. "Antibody-enzyme conjugates for cancer therapy." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500308.
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Advances in cancer therapy have led to the exploitation of the biological differences between cancer and normal cells. A popular approach is to attach a targeting moiety such as an antibody to a toxin or toxic enzyme in order to specifically locate and kill cancer cells only. However, many immunotoxins have fared poorly in their clinical trials, having shown to elicit immunogenic responses and toxicity in the patient. This problem is commonly attributed to the non-human sources of the toxins and enzymes being delivered. Targeting cytotoxic agents from human sources is therefore a prospective solution. Accordingly, this project aims to develop an immunoconjugate using mammalian or 'mammalian-like' enzymes for the treatment of epithelial cancers over-expressing the MUCl tumour antigen.
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Oakley, Ruth Elizabeth. "Molecular therapy for residual squamous cancer." Thesis, King's College London (University of London), 2003. https://kclpure.kcl.ac.uk/portal/en/theses/molecular-therapy-for-residual-squamous-cancer(720be9f3-65fd-4ea6-a65d-7a7f08793c46).html.
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A major problem in head and neck cancer management is the high rate of loco-regional recurrence following surgery and post-operative radiotherapy. Tumour cells that remain in the surgical margins are the likely source for this recurrence. Gene-mediated approaches, that take advantage of the genetic profile of these tumours, have the potential to eliminate these remaining cells. The high frequency of p53 mutation in head and neck cancers makes this gene a good candidate for therapy. The majority of residual cancer models used for treatment investigations are established subcutaneously in immunodeficient hosts. However, residual cancer models in muscle of immunocompetent hosts would more closely mimic the clinical scenario. In vitro studies established the suitability of the p53 mutated PDVC57 cell line for adenoviral-p53-mediated tumour destruction. PDVC57 cells showed 70% transduction efficiency. Polymerase chain reaction, Western blotting and immunocytochemistry confirmed the expression of the p53 transgene. Western blot analysis demonstrated increases in p21 WAFl, MDM2 and BAX proteins following Ad5CMV-p53 transduction. A significant reduction in PDVC57 number was observed following transduction of 625 vp/cell Ad5CMV-p53. The TUNEL assay and acridine orange/ethidium bromide incorporation suggested apoptotic death in 50010 and 70% of PDVC57 cells 48 hours after transduction with 2500 vp/cell Ad5CMV-p53 respectively. A new model of residual cancer was established by implanting 1 x 105 PDVC57 cells into the muscle of syngeneic immunocompetent hosts, and its reproducibility demonstrated. The reduction in tumour area following cisplatin treatment demonstrated the potential of this model for examining treatment efficacy. However, infection with 5 x 1010 vp Ad5CMV-p53 failed to destroy tumour in the muscle, likely due to the insufficient expression of the transgene. In comparison, Ad5CMV-p53 infection of a PDVC57 derived subcutaneous model of residual cancer, eliminated tumour in 4/6 cases. These studies highlight the requirement for improved gene delivery strategies for tumour in muscle.
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Chen, Ming-Jen. "Combination gene therapy for colorectal cancer." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273724.
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Oncolytic virotherapy with the adenovirus mutant dl 1520 in combination with chemotherapy has shown clinical response. Approaches to cancer gene therapy involving delivery of enzymes to activate the prodrugs CB 1954 and 5-FC are currently being tested in clinical trials. We hypothesised that the combination of an adenoviral vector equivalent to dl1520 with activation ofCB 1954or 5-FC and the combination of CB 1954 activation with 5-FU may further improve the antitumour effects for colorectal cancer therapy. The initial in vitro data showed that the combination of dl 1520 with CB 1954 activation or 5-FU (metabolite of 5-FC activation) and the combination of CB 1954 activation with 5-FU led to an additive or synergistic cytotoxicity. Subsequent data showed that the incorporation of Ntr or CD-UPRT genes into replicating oncolytic adenoviruses (ROAds) resulted in enhanced Ntr expression or CD-UPRT activity and augmented cytotoxic effects in tissue culture, surpassing the levels and cytotoxic effects mediated by the corresponding replication-defective vectors. When tested in subcutaneous human colon cancer xenografis, Ntr expression mediated by the ROAd was apparently higher than the level mediated by replication-defective CTLI02. Importantly, the antitumoural efficacy of CB 1954 activation mediated by ROAd is significantly superior to that mediated by CTLI 02 (p = 0.01). The ROAds displayed viral replication and oncolysis in vitro and in vivo and these attributes can contribute to the increased gene expression level and enhanced efficacy. Overall, the data suggested that the use of ROAds improved Ntr or CD-UPRT expression and antitumoural efficacy in the presence of corresponding prodrugs and may have the potential to achieve clinical significance in the treatment for colorectal cancer.
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Chung-Faye, Guy Allen. "Gene therapy strategies for colorectal cancer." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246708.
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Zweiri, Jehad Ahmed. "Suicide immune gene therapy of cancer." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270793.
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Luengo, Alba. "Examining metabolic vulnerabilities for cancer therapy." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/117787.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged student-submitted from PDF version of thesis. Vita.
Includes bibliographical references.
Metabolic reprogramming is essential for cancer cells to balance energetics, maintain redox homeostasis, and synthesize biosynthetic precursors. Many chemotherapeutics that target metabolism are essential components of standard cancer treatment regimens, arguing that there is a therapeutic window to target the metabolic dependencies of cancer cells. However, the use of these drugs as cancer therapies was determined empirically, and rational approaches to directly target the metabolism of cancer cells, especially reprogrammed glucose metabolism, have proved challenging, in part because it is not well understood which metabolic processes are most important for cancer cell proliferation and survival. The goal of this dissertation is to explore metabolic pathways preferentially used by cancer cells in order to identify potential tumor dependencies that could be exploited for clinical benefit. We first determined that production of reactive byproducts is an indirect consequence of the altered glucose metabolism of cancer cells, which suggests that clinically targeting secondary effects of reprogrammed tumor metabolism could be an approach for designing novel cancer treatments. Next, we found that a molecular driver for the altered glucose metabolism of cancer cells is limited electron acceptor availability, suggesting that interventions that further restrict the oxidative capacity of tumors could also have anticancer efficacy. Finally, we interrogated the metabolic fluxes of breast cancers proliferating in different microenvironments and determined that tumors in the brain parenchyma display enhanced lipid biosynthesis, which could guide therapeutic strategies to treat cancer based on tumor site. Collectively, these studies contribute to an understanding of how the reprogrammed metabolism of cancer cells introduces targetable dependencies, with the aim of optimizing cancer therapies.
by Alba Luengo.
Ph. D.
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McGinley, Susan. "Sensitizing Tumor Response to Cancer Therapy." College of Agriculture and Life Sciences, University of Arizona (Tucson, AZ), 2008. http://hdl.handle.net/10150/622086.
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Morrison, Rachel Anne. "Novel embolic particles for cancer therapy." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:ffbb74b6-0be8-4b02-b6f1-66484e706839.
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The aim of this thesis was to develop novel embolic particles for cancer therapy using a combination of nano and microparticles. The particles have been designed and synthesised to have a polystyrene core, be radiopaque, act as a radiosensitiser and have a high capacity for loading of chemotherapy drugs. The polystyrene core has been designed so it effectively blocks the tumour vasculature thereby limiting oxygen and nutrient delivery to the tumour thus causing tumour necrosis. The core of the polystyrene particle incorporates tantalum oxide nanoparticles to provide X-ray contrast to the embolic microparticles. The surface of the polystyrene particle has been coated with rare earth doped titanium dioxide (TiO2) nanoparticles which produce reactive oxygen species upon X-ray activation. This allows the embolic particle to act as a radiosensitising agent and has been shown to reduce cell proliferation in the presence of X-rays. The surface of the polystyrene particles has also been coated with mesoporous SiO2 nanoparticles which allow for the high loading capacity of chemotherapeutic drugs. This permits chemotherapy to be delivered directly to the tumour location, thereby reducing the toxic side effects of systemic treatment. As a proof of concept, the chemoembolization particles have been loaded with a novel fungal derived chemotherapeutic Ophiobolin A and the controlled release has been demonstrated. The OphA chemoembolization particles reduced cell viability by approximately 70% compared to the blank chemoembolization particles. The mechanism of cell death of OphA on eight cancer cell lines and one control cell line has also been studied and its effect on cellular organelles elucidated. OphA shows great promise as a novel chemotherapeutic which could be taken forward to animal trials.
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Dial, Christian W. "Adaptive Radiation Therapy for Lung Cancer." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3579.
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Prognosis for lung cancer patients remains poor. For those receiving radiation therapy, local control and survival have been shown to improve with increased doses; however, deliverable dose is often limited by associated toxicity. Therefore, methods that reduce dose to normal tissues and allow isotoxic escalation are desirable. Adaptive radiation therapy seeks to improve treatment by modifying the initial plan throughout delivery, and has been shown to decrease normal tissue dose. Studies to date suggest a trend of increasing benefit with increases in replanning frequency; however, replanning is costly in terms of workload and past studies implement at most weekly adaptation. The purpose of this thesis is to quantify the benefit associated with daily replanning and characterize the tradeoff between replanning frequency and adaptive benefit. A software tool is developed to facilitate planning studies and to introduce complimentary methods for evaluating adaptive treatments. Synthetic images and contours are xii generated for each fraction of a typical fractionation schedule using principal component analysis and a novel method of sampling coefficients that preserves temporal trends in the data (e.g. tumor regression). Using the synthetic datasets, a series of adaptive schedules ranging from no adaption to daily replanning are simulated and compared to quantify adaptive benefits and characterize tradeoffs with frequency. Daily replanning resulted in significant reductions in all normal tissue planning metrics when compared to no adaptation, and incremental reductions were observed with each increase in replanning frequency while the magnitude of average reductions decreased with each step. Modest correlation between absolute change in planning target volume over the course of treatment and reductions in both mean lung dose and mean esophageal dose were observed.
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Brown, Iain. "Gene therapy for sporadic ovarian cancer." Thesis, University of Aberdeen, 2000. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602008.
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Ovarian cancer accounts for more deaths than all other gynaecological cancers taken together. The 5 year survival rate can be as high as 80% for cases diagnosed early, but the asymptomatic nature of the disease means that it is most frequently detected in the later stages. By this time, disease has invariably spread beyond the ovaries and the survival rate drops to around 30%. Treatment of ovarian cancer often fails due to a high rate of chemoresistance and novel methods of treatment and detection are required to increase the survival chances of patients. This study sought to determine whether gene therapy for sporadic ovarian cancer could offer a novel and more successful treatment option for the disease. Mutation or abnormal expression of the p53 gene has already been shown to be the most common genetic even in ovarian cancer, being involved in up to 70% of cases. Wild-type p53 was delivered, using liposomes, into p53 mutant ovarian cancer cell lines and this resulted in a restoration of the wild-type functions of the gene, namely cell cycle arrest and apoptosis. The results from the cell line studies suggested that restoration of the wild-type p53 function limit or reduce tumour progression and increase the sensitivity of the tumour to chemotherapy. A mouse model of human peritoneal ovarian cancer was then constructed and the wild-type p53 gene was administered in liposomes into the peritoneum. The results suggested that p53 gene therapy prevents tumours from growing in the mice, when compared to a control gene. It is now known that p53 gene therapy for humans is being clinically assessed. There are a proportion of tumours that do not harbour an abnormal p53 gene, raising the possibility that other tumour suppressor gene mutations may play a role in the molecular genetic control of growth arrest and apoptosis. P53-dependent, apoptosis-regulating family members bcl-2 and bax were analysed immunohistochemically to determine their involvement in ovarian cancer. Both proteins were significantly associated with malignancy and also with overall length of survival, but not associated with the various prognostic factors such as stage and differentiation of tumour. It is unlikely that these genes will become targets for gene therapy in ovarian cancer. Mutation, deletion and hypermethylation of the p53-independent pi6 gene, alter its function, resulting in loss of G1 cell cycle arrest control. The status of methylation of the pi 6 promoter in ovarian tumours was determined and combined with mutation data, resulting in the conclusion that abnormal pi 6 was not a common event in ovarian cancer and is therefore not a likely candidate for gene therapy. This study has contributed to the evergrowing wealth of knowledge on the molecular genetic events of ovarian cancer, and has shown that gene therapy for sporadic ovarian cancer as a clinical application is feasible.
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Rayburn, Elizabeth R. "Novel immunomodulatory oligonucleotides for cancer therapy." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/rayburn.pdf.
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Scott, Susan Lynne Pipes. "Enhancing radiation therapy for prostate cancer /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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