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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

The chemical synthesis of natural and novel β-acid derivatives for biological evaluation as anticancer and antibacterial agents

Tucknott, Matthew L. January 2013 (has links)
The Tyrrell group has, in recent years, developed a strong interest in the chemical synthesis and biological activity of the hop bitter acids lupulone 1, humulone 2 and their naturally occurring congeners, 1 a-d and 2a-d. Previous work focused on investigating the chemistry of the a-acid humulone 2, demonstrating the propensity of this compound to have a cytotoxic effect against the SK-MES lung cancer cell line and the MCF-7 breast cancer cell line. This thesis documents the recent research concerning the synthesis, the anticancer and antibacterial activity of the ß-acid lupulone 1, its naturally occurring congeners 1 a-d and further, novel, non-naturally occurring compounds. We resumed the group's previous collaboration with the Golston and Pirianov research group at St Georges, where the anticancer studies were performed. The synthesis centred on a Friedel-Crafts acylation of phloroglucinol 32, followed by a C-trialkenylation reaction between the acylphloroglucinol and an allyl bromide. We conducted experiments that focused upon the choice of base and solvent for the trialkenylation reaction, concluding that liquid ammonia as both the base and solvent offered the most efficient route to the ß-acids. It was shown that aliphatic allylic bromides lend themselves to the' reaction, . although some derivatives require purification by column chromatography in addition to recrystallisation. In contrast, aromatic allyl bromides did not participate in the alkenylation reaction. We further investigated an alternate G-alkenylation reaction involving the di¬lithiation of 1,3,5-trimethoxybenzene. We discovered that by including copper (I) iodide in the reaction, prenyl bromide 23 and allyl bromide 41 could be successfully coupled. VVe also discovered that our 2nd generation ß-acids 42a-g could participate in a ring-closing metathesis reaction, forming novel spirocyclic compounds 50a-b. Our antibacterial studies showed that ß-acids are effective against Gram-positive bacteria, but not Gram-negative bacteria in accordance with published observations. We took our investigations further and found that ß-acids are effective against mutlidrug-resistant 'Staphylococcus aureus', even where the commercially available ciprofloxacin 67 was not.
12

The biological and clinical significance of HER family members and cancer stem cells in colorectal cancer and response to therapeutic interventions

Khelwatty, Said Abdullah January 2012 (has links)
Despite the approval of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) cetuximab and panitumumab for the treatment of colorectal cancer patients, there is currently no reliable predictive marker for response to therapy. EGFR is the prototype of human epidermal growth factor receptor (HER) family, which includes three additional members namely HER-2, HER-3 and HER-4. The aim of this study was to investigate the sensitivity of a panel of human colorectal cancer cell lines to treatment with afatinib, an irreversible pan-HER blocker, the EGFR tyrosine kinase inhibitors (TKls) gefitinib and erlotinib, anti-EGFR mAb ICR62 and cytotoxic drugs and to determine whether there was any association between the expression levels of HER family members, the putative cancer stem cell (CSC) markers CD44 and CD133 and ABC transporters (e.g. p-glycoprotein) and response to these agents. The expression pattern and clinical significance of these markers in tumour specimens from 86 Dukes' C and D colorectal cancer patients was determined. Overexpression of the HER family members were found to be uncommon in this panel of human colorectal cancer cell lines, except for EGFR overexpression in DiFi cells. Of the HER inhibitors, afatinib was the most effective agent for inhibiting the growth in vitro of human colorectal cancer cell lines and the expression of HER -4 alone and the co-expression of all the HER family members were associated with response to treatment with afatinib. Acquired resistance of the EGFR overexpressing colorectal cancer cells to treatment with afatinib, ICR62 or gefitinib was accompanied by the up-regulation of EGFR. However, tumour cells that acquired resistance to anti-EGFR mAb ICR62 remained sensitive to treatment with afatinib and vice versa, suggesting that mechanisms underlying the antitumor activity of ICR62 and afatinib are different. The expression ofEGFR, HER-2, HER-3, HER-4 and co-expression of all the HER family members was found in 42.5%, 77%, 52%, 91 % and 18% of the tumour specimens from 86 Dukes' C and D colorectal cancer patients respectively. While all the patients expressed COX-2 and Ki-67, the expression ofCD44 and CD133 was found in 58.6% and 81.9% of the cases, respectively. The expression of EGFR and low expression of Ki-67 were found to be significantly associated with poor disease free survival. The co-expression of HER family members in colorectal cancer patients provides a rationale for investigating the pattern, prognostic significance and predictive value of the HER family members for response to therapy with anti-EGFR mAbs. Further investigations in vivo on the therapeutic potential of pan-HER blockers, such as afatinib, in colorectal cancer patients whose tumours co-express more than one member of the HER family should also be considered.
13

Efficacy of resveratrol metabolites on colon cancer cell growth

Polycarpou, Elena January 2013 (has links)
Resveratrol is a natural polyphenol present in many plant species and derived foods including grapes and red wine. It has been shown to possess chemotherapeutic properties in animal cancer models as well as many biological effects in vitro. In this study, the effects of three resveratrol metabolites including resveratrol-3-0-D-glucuronide, resveratrol-4'-O-D-glucuronide and resveratrol-3-0-D-sulphate on the growth of colon cancer cell lines have been investigated. The growth inhibitory effects of resveratrol, piceatannol, pterostilbene and the glucuronide and sulphate metabolites on Caco-2, CCL-228 and HCT-116 cells were assessed using the neutral red and MTT assays. Resveratrol and its metabolites inhibited the growth of cells with ICso values in the range of 9.8-31 f.lM whilst piceatannol and pterostilbene in the range of 21.7-29.6f.lM and 5-34.5f.lM respectively. Apoptotic assessment by DAPI staining, Z-VAD-FMK pre-treatment and percentage of cells in sub-Gl by FACS all revealed the absence of apoptosis. Treatment of differentiated Caco-2 mono layers showed that resveratrol was capable of inhibiting the growth of cells following treatment on the apical but not basolateral membrane and the effects were less profound with the metabolites. Only high concentrations (500f.lM) of metabolites (not used in any ofthe growth studies) appeared to be toxic to normal cells as measured by a haemolysis assay. Resveratrol was capable of causing S phase arrest in all 3 cell lines at 30f.lM whilst the two glucuronides caused GO/GI arrest in Caco-2 and CCL-228 cells only. Resveratrol-3-0-D-sulphate had no effect on the cell cycle. Growth inhibition caused by resveratrol and its two glucuronides was reversed by the addition of an AMP kinase inhibitor (compound C) or an adenosine A3 receptor antagonist (MRS-119l). Treatment with the highly selective A3 receptor agonist, 2CI-m-MECA caused growth inhibition and the A3 receptor was 'detected in all 3 cell lines. Levels of eyelin D 1 as measured by western blot were significantly reduced at higher concentrations (lOOf.lM) but p-AMPK was not reliably increased in all cases. Resveratrol glucuronides were shown to inhibit the growth of three colon cancer cell lines by GO/G 1 arrest and depletion of eyelin D 1. These findings strongly suggest a role of the adenosine A3 receptor in the observed inhibition therefore, providing a novel target for resveratrol and its metabolites.
14

Biofilm formation and characterisation in human mycoplasmas

Awadh, Ammar A. January 2014 (has links)
Mycoplasmas are the smallest and simplest self-replicating prokaryotes, lacking a cell wall and are bound by a single membrane-the plasma membrane. Moreover, mycoplasmas are consequential and chronic pathogens of humans and animals that rely on adhesion to host tissue for colonisation and infections. In other word biofilm formation is correlated with infections and because of this, the biofilm formation of Mycoplasma species has been investigated and characterised in this project. The viability of biofilm formation was assessed and quantified using crystal violet assay over 20-day incubation period. It was noticed that some mycoplasma isolates were capable of forming biofilms more readily than others, which in turn revealed a striking variability in the ability'of Mycoplasmas species to form biofilms. Mycoplasma biofilms and planktonic cells were exposed to environmental stresses, including heat and desiccation to determine their resistance to these stresses. The experiment revealed that mycoplasma biofilms were more resistance to stresses than their planktonic counterparts. The architecture of mycoplasma biofilms was analysed using the combination of two visualisation techniques; CLSM and SEM to determine growth dynamics as well as quantify the biofilm volume over time. The experiment showed that the volume of biofilm become greater when the biofilm gets older. The metabolic patterns of Mycoplasma fermentans and Mycoplasma pneumoniae biofilm cells was investigated and comparing them with their planktonic counterparts in order to characterise the metabolomic changes between planktonic and biofilm cells and thus observe how far their metabolic activities are different.
15

An investigation of the effects of selected Chinese herbal remedies on cancer cells 'in vitro'

Willimott, Shaun January 2007 (has links)
Chinese herbal remedies (CHRs) are commonly prescribed for the treatment of cancer, however their use is often based on the belief systems of traditional Chinese medicine (TCM), and there is relatively little information regarding their efficacy or biological action. Thus, the aim of this investigation was to select a range of CHRs with some suggestion of tumour modulatory activity, and to devise and implement a strategy with which to investigate their direct toxicity to cancer cells, in an attempt to elucidate their potential efficacy and mode of action. The CHRs ‘OldenIandia diffusa’ (OD), Long Dan Xie Gan Wan (LD), ‘Polygonum multiflorum’ (PM) and ‘Polyporus umbellatus’ (PU) were selected for this investigation, and their direct cytotoxic potential against cancer cells examined using an ‘in vitro’ cell-based system. Initially, water and ethanol extracts of each CHR were made and their toxicity evaluated against a range of cancer cell lines (HL60, HT29, HCT-8, HeLa and CHO). The results of this study suggested that water extracts of OD, LD and PM, but not PU, were significantly toxic to a range of cancer cell types. Further investigation (using the HL60 and HT29 cell lines) suggested that OD and LD induced apoptosis in cancer cell lines ‘in vitro’ through activation of the intrinsic pro-apoptotic signalling pathway (characterised by activation of caspase 9), possibly through the induction of genotoxic damage, and that this activity was related to the combined actions of a number of cytotoxic compounds, and not to a single constituent. Furthermore, OD and LD were found to be less toxic to cultured primary blood lymphocytes (PBLs), thus further suggesting that there may be some scientific basis for their use in the treatment of cancer. Further investigation into the cytotoxic action of water extracts of PM revealed that it was inducing necrosis in cancer cell lines and not apoptosis, thus suggesting that PM does not possess anticancer activity. Overall, the results of this investigation suggest that OD and LD may be a source of novel chemotherapeutic agents, and that there may be some scientific basis for their traditional use in the treatment of cancer.
16

An evaluation of the use of the Taguchi methods to investigate complex biological interactions in acute lymphoblastic leukaemia

El-Morsi, Hisham January 2001 (has links)
The control of proliferation, differentiation and survival of normal and malignant haemopoietic cells is under the control of a wide range of different factors. These include cell:cell interactions, immune regulatory factors, hormonal influences, and local environmental influences. However, the way in which these factors combine to regulate the dynamics of the leukaemic cell are poorly understood. One of the main problems in conducting these experiments is the logistical difficulty in comparing multiple variables. For example, to design an experiment to simulate and study a biological system that involves 13 factors each at 3 different levels requires 1,594,323 experimental runs. Taguchi methods, on the other hand, use orthogonal arrays to create smaller, less costly experiments that have a high rate of reproducibility. A study involving 13 factors at 3 different concentrations can be conducted with only 27 experimental runs. The use of Taguchi methods in the discipline of life scienceis in its very early stages, as very limited number of experiments in this field have been designed and analysed according to the Taguchi methodology. This study was thus set to investigate the suitability of Taguchi methods to study a biological problem with multiple factors involved and poorly understood mechanisms.
17

Synthesis and biochemical evaluation of potential steroidal and non-steroidal inhibitors of 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD) in the treatment of hormone-dependent cancers

Olusanjo, Moniola Sarah January 2008 (has links)
Enzymes such as aromatase, 17[beta]-hydroxysteroid dehydrogenase [types 1 (17[beta]-HSD1) and 3 (17[beta]-HSD3)] and estrone sulfatase (ES) are all involved in the biosynthesis of steroids via the steroidal cascade. The inhibition of these enzymes may lead to a reduction in the levels of steroids present, thereby leading to a decrease in the stimulation of hormone-dependent tissues, in particular, hormone-dependent breast and prostate cancers. This approach has proved to be successful in postmenopausal women where the use of aromatase inhibitors has led to the decrease in tumour yield and has thus led to the treatment of the disease. Within the current study, the synthesis and biochemical evaluation of a number of compounds of varying structural features has been undertaken, in particular, the synthesis of sulfonate derivatives of 4-hydroxyphenyl ketone - the parent compound having already been shown to be a potent inhibitor of 17[beta]-HSD3 (with good specificity towards 17[beta]-HSD3) and the synthesis of a range of alkyl and cycloalkyl esters of steroids [in particular, testosterone (T) dehydroepiandrosterone (DHEA) and estrone (E10] as probes of the active sites of the HSD family of enzymes. The results show that the sulfonate (methanesulfonate and trifluromethanesulfonate) derivatives of 4-hydroxyphenyl ketone-based compounds were found to possess weak inhibitory activity against all three HSD enzymes considered (namely, 17[beta]-HSD1, 17[beta]-HSD3 and 3[beta]-HSD) in comparison to the parent 4-hydroxyphenyl ketone-based compounds. For example, within the methanesulfonate derivatives, methane sulfonic acid (4-cyclohexane carbonyl)-phenyl ester (164) was found to be the most potent inhibitor against 17[beta]-HSD3, however, it possessed ~30% inhibitory against this enzyme at an inhibitor concentration of 100[mu]M. Against 17[beta]-HSD1, the most potent compound within the same range was also compound 164 which pssessed ~45% inhibitory activity under similar conditions. Within the trifluromethane sulfonate derivatives, the most potent compounds proved to be extremely weak inhibitors of 17[beta]-HSD3, however, against 17[beta]-HSD1, the most potent compound was trifluromethane sulfonic acid 4-benzoyl-phenyl ester (180) which possess 43% inhibitory activity. The molecular modeling of these compounds within representations of the active sites of 17[beta]-HSD1 and 17[beta]-HSD3 shows that the lack of inhibitory activity is due to steric hindrance, in particular, the sulfonate moeity undergoes steric hindrance with groups at the active site which is close to the C(17) area of the natural substrate. The synthesis of the esters of T, DHEA and E1 and the subsequent biochemical evaluation of these compounds resulted in an interesting structure-activity relationship. In general, the compounds based on DHEA were found to be potent inhibitors of 17[beta]-HSD3 with weak inhibitory activity against 17[beta]-HSD1 and 3[beta]-HSD. For example, DHEA acetate (196) was found to possess an IC[sub]50 value of 0.74[mu]M in comparison to the most potent standard, namely 1-(4hydroxy-phenyl)-nonan-1-one (139) which was found to possess an IC[sub]50 value of 12.32[mu]M - this compound was found to possess good selectivity as it possessed ~40% and ~25% inhibitory activity against 17[beta]-HSD1 and 3[beta]-HSD respectively at an inhibitor concentration of 100[mu]M. The esters of E1 and T proved to be weaker inhibitors in comparison to the esters based on DHEA, however, the E1-based esters also showed some selectivity towards 17[beta]-HSD3. For example, E1 hexanoate (216) possessed an IC[sub]50 value of 37.28[mu]M and possessed 45% and 35% inhibitory activity against 17[beta]-HSD1 and 3[beta]-HSD respectively at an inhibitor concentration of 100[mu]M. The modelling of these compounds (using representations of the active sites of 17[beta]-HSD1 and 17[beta]-HSD3) showed that the lack of inhibitory activity was due to steric interactions between the inhibitors and groups within the active site. As such, these compounds proved to be extremely useful probes of the active sites of 17[beta]-HSD1 and 17[beta]-HSD3 and have further enhanced the models used in the design of these compounds.
18

Growth, survival and cell death in the epithelial cell lines HaCaT, HT29 and SW742

Bretland, Amanda Jane January 1998 (has links)
No description available.
19

The synthesis of imidazole derivatives for the inhibition of steroid-mediated prostrate tumour growth

Jandu, Baljeet Kaur January 2013 (has links)
The majority of prostate cancer cases are shown to be androgen-dependant for growth as the blocking of androgen production has shown to reduce the size of prostate metastasis. The biosynthesis of the androgens is catalysed by the cytochrome P450 enzyme 17a-hydroxylase/17,20-lyase (P45017a) by converting the C21 steroids (pregnenolone and progesterone) to the androgens (dehydroepiandrosterone and androstenedione, respectively). Inhibition of P45017a would therefore bring about a decrease in the level of androgen production and furthermore prevent an increase in the stimulation of androgen-dependent prostate cancer cells. The current study was concerned with designing and synthesising compounds which were able to donate a lone pair of electrons to the Fe atom of the haem group with in the active site of the enzyme P45017a. As well as this, we were also interested in being able to mimic the C(3) of the natural substrate by varying the R group. In doing so, we were able to observe the impact of the interactions which take place within the active site. The compounds synthesised are based on the benzyl imidazole and the imidazolphenyl ethanonebackbone, where a small number of the synthesised products are phenyl alkyl imidazole based compounds, in order to consider physiochemical factors like hydrophobicity. Overall, the results of the study showed that the benzyl imidazole-based compounds were comparable to that of the standard ketoconazole (KTZ) in their inhibitory activity against 17,20-lyase and 17a-OHase (KTZ; %inhibition = 75% against 17,20-lyase: %inhibition = 64% against 17a-OHase). The nitro substituted derivatives (270-272) were shown to have improved inhibitory activity when compared to KTZ against 17a-OHase. With respect to the imidazol-phenyl ethananes, all with the exception of the 3-bromo substituted derivative ~88) were shown to possess either equipotent inhibitory activity to that of KTZ (%inhibition = 80% against 17a-OHase: %inhibiton = 82% against 17,20-lyase) or substantially lower activity. Compound 288 was found to possess greater inhibitory activity against the 17a-OHase component (288 %inhibition = 84%). Deliberation of structure-activity relationships determined no obvious correlation between the substitution pattern of the benzyl ring and the inhibitory activity against 17,20-lyase in the benzyl imidazole-based compounds. However, in the activity against 17a-OHase, a general trend towards the para substitution of the benzyl ring was shown to have an impact on the inhibition of the enzyme. In the imidazol-phenyl ethananes, consideration of the inhibitory activity of the halogen derivatives shows that there is an increase in potency with decreasing electronegativity of substituent group. In the inhibitory activity against 17a-OHase, some compounds show a correlation between decreasing electron-withdrawing ability and an increase in percentage inhibition. This would therefore appear to suggest that an ·interaction exists between the substituent and complementary group(s) at the active site of the enzyme - this interaction appears to be weaker within derivatives which possess substituents of high electronegativity. The substitution of the phenyl ring was too shown to influence the inhibitory activity of the compounds, which was rationalised by use of the SHC approach. This was proposed as results clearly indicate that the meta-substituted compounds were found to possess greater inhibitory activity in comparison to the para-substituted compounds.
20

Semi-automatic quantitative assessment of cancer-cell invasion 'in vitro' : an image-processing approach

Hagglund, Samuel January 2009 (has links)
In western countries at least one third of the population develops cancer. The main cause of death in cancer patients is metastasis and there is no effective treatment for this complication. The situation can be improved by a better understanding of the cancer invasion process. In order to re­ veal new aspects of this dynamic process, a novel image-processing-based direct viewing cancer-cell invasion assay was developed and used with inverted wide-field microscopy. The combination of high-resolution 3D image-processing approaches with a custom-made flow chamber system enabled the quantification of the sarcoma-cell invasion process through a monolayer of endothelial cells in vitro. The image processing entailed the separation of positive cell signal from background noise and blur, which are inherent in 3D wide-field microscopy. The preparation and cell signal segmentation of wide-field images prior to quantification featured stochastic as well as deterministic techniques. The stochastic approach was based on a Gaussian Mixture Model to separate noise and background signal characteristics from positive cell signal which performed well in conditions with high signal-to-noise ratios. The. deterministic segmentation approach was based- on linear diffusion and performed well despite low signal-to-noise ratios as it assessed the diffusion rates of cell signal over multiple convolutions. The image-processing-based assay included the definition of two new parameters to quantify the invasion: Relative Invasion (RI) and Opening Rate of the Endothelial Monolayer (O REM). The first parameter RI measured the invasion as the percentage of sarcoma cell signal below the reconstructed monolayer surface. The second parameter O RE M evaluated the speed at which the sarcoma cells disassemble the monolayer in their strive to exit the flow channel. This assay was applied to metastatic rat sarcoma cells where the cells invaded monolayers of rat endothelial cells. After adhesion, the sarcoma cells initially invaded significantly faster under flow conditions compared to situations without shear stress. Later, however, the rate of invasion underflow decreased and the sarcoma cells without shear stress achieved significantly higher levels of invasion. These observations thus revealed the non-linear modulation of a tumour-cell invasion process by shear flow, demonstrating that tumour cells can respond to flow by enhancement of invasiveness in a similar way to white blood cells. In summary, the newly developed direct viewing assay provides a quantitative image-processing-based approach to assessing cancer invasion dynamics, which should lead to a better understanding of the mechanisms involved in cancer invasion and metastasis.

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