Dissertations / Theses on the topic 'Anti-cancer drugs'
To see the other types of publications on this topic, follow the link: Anti-cancer drugs.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Anti-cancer drugs.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Yeh, Teng-Kuang. "Pharmacokinetics of anti-aids and anti-cancer drugs : implications on drug delivery and drug interaction /." The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu148654688938101.
Full text
2
Soldevila, Barreda Joan Josep. "Design of catalytic organometallic anti-cancer drugs." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/63808/.
Full textAbstract:
This thesis is concerned with the design of organometallic half sandwich complexes which can catalyse the conversion of oxidised coenzyme nicotinamide adenine dinucleotide to its reduced form. The coenzyme pair NAD+/NADH is involved in many biological processes, such as regulation of the redox balance, and DNA repair. Disturbance of the NAD+/NADH ratio can lead to cell death. In particular, cancer cells are under constant oxidative stress and therefore might be more susceptible to changes in the NAD+/NADH levels. A series of neutral Ru(II) complexes of the type [(η6-arene)Ru(N,N’)(L)] (arene = p-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), benzene (bn); N,N’ = N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-toluensulfonamide (TsEn), or N-(2-aminoethyl)-4-methylensulfonamide (MsEn)) were synthesized and fully characterized. The complexes were shown by 1H-NMR to catalyse region-selectively the transfer hydrogenation of NAD+ to 1,4-NADH. Comparison of the turnover frequencies (TOF) for the complexes show a trend in which a decrease in catalytic activity with the arene ligand follows the order bn > bip > p-cym > hmb and TfEn > TsEn > MsEn. Complex [(η6-bn)Ru(TfEn)Cl] (12) was found to be the most active with a TOF of 10.4 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied for complex [(p-cym)Ru(TsEn)Cl] (2). The monotosylate ethylenediamine Ru(II) complexes were used to carry out, for the first time, transfer hydrogenation reactions in cellulo (A2780 ovarian cancer cells) using formate as a hydride source. The antiproliferative activity of six complexes on co-administration with non-toxic doses of sodium formate were studied. A significant potentiation of the antiproliferative activity by formate was observed. The concentrations of NAD+ and NADH in cells showed an important reduction in the NAD+/NADH ratio. This study demonstrates that it may be possible to use catalytic transfer hydrogenation as a strategy for multi-targeted redox mechanisms of action for anticancer drugs. In order to compare the anticancer mechanism of the monotosylate ethylenediamine Ru(II) complexes with the corresponding ethylenediamine (en) complexes, DNA binding studies were carried out. The complexes were shown to bind to nucleobases only moderately strongly and no direct coordination to calf thymus DNA was observed. The complexes can destabilize DNA, but they display low affinity towards DNA, which suggests that DNA is probably not involved in the mechanism of these family of compounds. Interaction of complex [(p-cym)Ru(TsEn)] (2) with glutathione (GSH) was also studied. The complex undergoes ligand substitution. Two Ru(II) dimers were formed as the main products of the reaction: ([((p-cym)Ru)2(μ-GS)3] and [((p-cym)Ru)2(μ-GS)2]). These dimers share structural similitudes with other reported Ru(II) arene anticancer drugs, which suggests that they could be responsible for the moderate antiproliferactive activity of complex 2. A series of CpxRh(III) (CpX = CpXPhPh, CpXPh or Cp*) complexes containing en or TfEn were synthesised and fully characterised. The complexes were shown to catalyse regioselectively the transfer hydrogenation of NAD+ to 1,4-NADH with higher TOF than their Ru(II) analogues. Rh(III)-en compounds were shown to be more active than the Rh(III)-TfEn analogues. The nature of the Cpx ring was shown to influence significantly the catalytic activity of the complexes following the trend: CpXPhPh > CpXPh > Cp*. Complex [(CpXPhPh)Rh(en)Cl]+ (19) was the most active, with a TOF of 24.2 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied using complex [(Cp*)Rh(en)Cl]+ (17) and compared to that of the Ru(II) analogues, and was found to be similar. Antiproliferative activity of the complexes in combination with formate, in A2780 cells, was investigated, but the potentiation due to the transfer hydrogenation was much lower than that obtained with Ru(II) compounds.
3
Butler, Gregory James. "Non-steroidal anti-inflammatory drugs and skin cancer /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19122.pdf.
Full text
4
Moorad, Razia. "Computer-aided drug design and the biological evaluation of anti-cancer drugs." Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/20715.
Full textAbstract:
Computer-aided drug design has become a promising alternative to high-throughput screening by identifying potential hits in silico for in vitro evaluation. In this study a combination of ligand-based and structure-based virtual screening was performed to identify in silico hits. This was based on finding similar inhibitors to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, a potent inhibitor of the Nuclear Factor kappa B (NF-κB), a transcription factor that has a pivotal role in cancer survival and Pentamidine, an anti-parasitic drug that has recently been demonstrated to possess tumour-killing activity. A hierarchical methodology consisting of a similarity search followed by structure-based virtual screening of the ZINC database was performed. In order to perform the docking studies, binding sites for 6-amino-4-(4-phenoxyphenylethylamino) quinazoline on the NF-κB/IκBα complex were identified through blind docking. In addition, the National Cancer Institute (NCI) database was screened, utilising existing structure-activity relationship data from literature. A pharmacophore search was designed to test the hypothesis of the structural features necessary for activity as seen with quinazoline inhibitors of NF-κB. No virtual hits from the ZINC database were confirmed with in vitro activity. On the other hand, three compounds identified from the pharmacophore search were confirmed to inhibit cancer cell proliferation in vitro, with compound NSC727152 demonstrating the most potent activity. In order to determine if NSC727152 acted similarly to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline by inhibiting NF-κB, the effects of NSC727152 on the expression of NF-κB targeted genes, including the Growth Arrest and DNA Damage 45 (GADD45) α and γ and the Interleukin 6 (IL-6) genes were evaluated. GADD45 α and γ have been shown to be regulated by NF-κB during cancer progression and aberrant IL-6 gene expression has been implicated in cancer progression and mortality and its expression is at least partially mediated via constitutive activation of NF-κB. In this study, it has been demonstrated that GADD45 α and γ are upregulated after treatment with NSC727152. A down-regulation of the IL-6 promoter activity and mRNA expression in cancer cells treated with NSC727152 has also been demonstrated in this study. However, no hits similar to Pentamidine were confirmed with in vitro activity. In conclusion, the compound NSC727152 has been shown to inhibit NF-κB and further analysis is necessary to determine its full potential as an NF-κB inhibitor.
5
Gascoigne, Karen Elizabeth. "The response of cancer cells to anti-mitotic drugs." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493935.
Full textAbstract:
In 2007 over 12 million people were diagnosed with cancer. At least one third of these individuals are not expected to survive the disease, making cancer the second most prevalent cause of death worldwide. Systemic chemotherapy forms the mainstay of cancer treatment. In particular, this thesis focuses on antimitotic drugs, which are now common chemotherapeutic agents used to treat a wide variety of cancers. These compounds have seen success in the clinic, however, patient response remains highly unpredictable and resistance to treatment is commonplace. Anti-mitotic drugs such as taxol and the vinca alkaloids are thought to inhibit tumour proliferation by disrupting formation of the mitotic spindle, preventing normal Prolonged mitotic arrest due to chronic activation of the spindle assembly checkpoint (5AC). It is presumed that this prolonged arrest leads to cell death, however, the molecular links between mitotic arrest and cell death are ill-defined.
6
Wahed, I. A. "Testicular toxicity of standard and investigational anti-cancer drugs." Thesis, University of Bradford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380578.
Full text
7
Abumansour, Hamza M. A. "Quantitative pharmacoproteomics investigation of anti-cancer drugs in mouse : development and optimisation of proteomics workflows for evaluating the effect of anti-cancer drugs on mouse liver." Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/15724.
Full textAbstract:
Minimizing anti-cancer drug toxicity is a major challenge for the pharmaceutical industry. Toxicity is most frequently due to either the direct interaction of the drug on previously unidentified targets or its conversion to metabolites by drug metabolizing enzymes (e.g. CYP450 enzymes) that cause cellular, tissue or organ damage. Pharmacoproteomics is beginning to take a central role in studying changes in protein expression corresponding to drug administration, the results of which, inform about the mode of action, toxicity, and resistance in pre-clinical and clinical stages of drug development. The main aim of this research is to apply comparative proteomics studies on livers from male and female mice xenograft models treated with major anti-cancer drugs (5-flourouracil, paclitaxel, cisplatin, and doxorubicin) and CYP inducer, TCPOBOP, to investigate their effect on protein expression profiles (proteome). Within this thesis, an attention is paid to optimise a highly validated proteomics workflow for biomarker identification. Proteins were extracted from liver microsomes of mice treated in two separate sets; Set A – male (5-fluoruracil, doxorubicin, cisplatin and untreated) or Set B – female (5-fluoruracil, paclitaxel, TCPOBOP and untreated) using cryo-pulverization and sonication method. The extracts were digested with trypsin ii and the resulting peptides labelled with 4-plex iTRAQ reagents. The labelled peptides were subjected for separation in two-dimensions by iso-electric focusing (IEF) and RP-HPLC techniques before analysis by mass spectrometry and database searching for protein identification. Set A and Set B resulted in identification and quantification of 1146 and 1743 proteins, respectively. Moreover, Set A and Set B recovered 26 and 34 cytochrome P450 isoforms, respectively. The microsomal changes after drug treatments were quite similar. However, more changes were observed in the male set. Up-regulation of MUPs showed the greatest distinction in the protein expression patterns in the treated samples comparing to the untreated controls. In Set A, 5-fluoruracil and cisplatin increased the expression of three isoforms (MUP1, 2, and 6), whereas doxorubicin has increased the expression of four isoforms (MUP1, 2, 3, and 6). On the other side, only TCPOBOP in Set B has increased the expression of two isoforms (MUP1 and 6). Our findings showed that the expression of MUP, normally involved in binding and excretion of pheromones, have drug- and sex-specific differences. The mechanism and significance of MUP up-regulation are ambiguous. Therefore, the impact of each therapeutic agent on MUP and xenobiotic enzymes will be discussed.
8
O'Riley, Hannah Adele. "Mechanisms of the Anti-Metastatic and Cytotoxic Properties of Ruthenium Anti-Cancer Drugs." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13881.
Full textAbstract:
Despite significant advances in the treatment of primary tumours through radiotherapy, surgery and chemotherapy; treatment and prevention of metastasis remains problematic. The benefits that traditional Pt chemotherapies have had on patient outcomes have been hampered by drug resistance and severe patient side-effects. These disadvantages have spurred fresh research into other metal-based pharmaceuticals and Ru complexes have been identified as promising drugs for cancer therapy. In this work, the mechanism of action of NAMI-A, KP1019 and other Ru complexes were investigated. A series of RuII complexes containing neutral face-capping sulfur macrocycle ligands, 1,4,7-trithiacyclononane ([9]aneS3), and 1,4,7,10-tetrathiacyclododecane ([12]aneS4) were synthesized, characterized and investigated to determine the significance of the kinetically driven activity of Ru drugs. As these Ru complexes ([RuCl2([9]aneS3)(S-dmso)], [RuBr2([9]aneS3)(S-dmso)], and [RuCl([12]aneS4)(S-dmso)]Cl) have structural similarities, relationships between the kinetic rates of halido ligand substitution (determined by UV-vis spectroscopy) and in vitro activity were established. The ligand 1,4,7-trimethyltriazacyclononane (Me3tacn), is a neutral face capped ligand investigated in this work. The reactivity and biological activity of the RuII/III trimer complex [Ru3Br6(Me3tacn)2]Br was studied. Previous studies have shown that Ru complexes such as NAMI-A and KP1019 behave as pro-drugs, and that their interaction with blood serum proteins is essential to their activity. Structural properties of the adducts of Ru with various serum proteins were revealed with the use X-ray absorption spectroscopy. The nature of Ru interaction with serum proteins was investigated with gel electrophoresis X-ray fluorescence mapping. This work provided insight into the nature of the reactions that occur when Ru pro-drugs are administered intravenously, and the results of these interactions on anti-cancer activity.
9
Zhao, Yunjie Physical Environmental & Mathematical Sciences Australian Defence Force Academy UNSW. "Cucurbit[n]uril - a delivery host for anti-cancer drugs." Publisher:University of New South Wales - Australian Defence Force Academy. Physical, Environmental & Mathematical Sciences, 2009. http://handle.unsw.edu.au/1959.4/44380.
Full text
10
Puri, Sanyogitta. "Novel functionalized polymers for nanoparticle formulations with anti cancer drugs." Thesis, University of Nottingham, 2007. http://eprints.nottingham.ac.uk/10316/.
Full textAbstract:
The chemistry and structure of Poly (glycerol adipate) facilitate its substitution with various pendant functional groups leading to modifications of the physicochemical properties of the polymer. Modified backbones then can be selected based upon the properties of the compound to be incorporated. Thus, this could be explored as a drug delivery system without many of the limitations of commercially available polymers. The aim of this study was investigate whether various polymers and drugs interact in a specific manner and whether the nature of these interactions influence the physicochemical characteristics of the particles and their drug loading and release profile. By investigating drugs belonging to various classes and with different properties it has been possible to correlate properties associated with drugs and pendant functional groups of the polymer which are ultimately responsible for the drug loading and release characteristics. For some drug polymer formulations, good loading and controlled release rates have been achieved. Compared to various conventional polymer systems reported for nanoparticle formulations, poly (glycerol adipate) polymers have also demonstrated the ability to control rate of release of highly water soluble drugs, even from the most hydrophilic polymer backbone in its unsubstituted form. From the various drug loading and release profiles it has been demonstrated that, unlike reported literature, particle size is not the primary factor influencing drug release over the relatively small range of particle sizes seen in this study. Neither is the water solubility of either the drug or the polymer alone responsible for the rapid and uncontrolled release profile from nanoparticles. Thus, Drug polymer interactions are more likely to influence drug loading and release and unlike common reports in the literature, hydrophilicity, molecular weight or concentration of polymer / drug are less likely to affect these parameters in isolation.
11
Al-Obaidi, Ahlam Ismail Ibrahim. "Examination of IKKα inhibitors as novel anti-panceatic cancer drugs." Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=30689.
Full textAbstract:
Pancreatic cancer has a very poor prognosis, it is the fourth most common cancer worldwide in terms of mortality, and it is expected to be the second most common within a decade. Most patients with pancreatic cancer are either resistante [sic] to chemotherapy or become so, thus surgery is the only choice with a considerable chance of tumour re-growth. Therefore an alternative treatment is urgently sought. The Nuclear Factor Kappa B (NFkB) cascade is comprised of two interdependent pathways, recognized as the classical pathway or canonical NFkB pathway, which is IKKB dependent, and IKKα-dependent non-canonical or alternative NFkB pathway. Studies have linked the hyper-activation of both pathways to pancreatic tumorigenesis. IKKβ inhibitors as a class of potential drugs for anti-cancer treatment have been accompanied by a number of issues regarding toxicity. IKKα has been implicated in a number of biological processes including cancer development, therefore targeting IKKα is a new approach for the development of pancreatic cancer therapies and is examined in this thesis. In chapter three, both NFkB pathways were characterised using different agonists; LTα1β2, TNFα and FCS. LTα1β2 stimulated the IKKα -dependent non-canonical pathway, inducing phosphorylation of p100 after 4h stimulation, while the maximum activation of p52 formation was between 24 and 48h. TNFα and FCS were without effect. TNFα and LTα1β2 stimulated the canonical NFkB pathway and taken together these studies indicated the presence of a functional non-canonical pathway. In chapter four, a number of novel IKKα inhibitors generated in-house, were also examined against both the non-canonical and canonical NFkB pathways. Three different effects were observed; selective inhibition of IKKα by SU1261, SU1411, SU1349, SU1433, SU1438 and 1434. Inhibition of both IKKα and IKKβ by (SU1087, SU1432, SU1499 and SU1436) and no inhibition of either pathway (SU1392). The effect of selective IKKα inhibitors on cell cycle and growth were also examined and confirmed that IKKα has a role in proliferation of pancreatic cancer cells. In chapter five, the expression of IKKα- dependent target genes was investigated using the agonist that activates the IKKα-dependent non-canonical NFkB pathway, LTα1β2. The findings confirmed that the expression of genes (BBC3, EZH2, TNFAIP3, VCAM, MAP3K14 and SERPINB6) was likely to be regulated through this pathway. This was confirmed using IKKα selective inhibitors, which resulted in the expression of all gene subsets were reduced [sic]. Taken together these data indicate that IKKα plays a key role in the regulation of the non-canonical NFkB pathway in pancreatic cancer cells and that selective inhibition IKKα may be a new strategy for developing anti-cancer drugs.
12
Guo, Canhui. "Mechanism of Anti-Cancer Activity of 9-Aminoacridine Based Drugs." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1216215825.
Full text
13
White, Alex William. "The design of novel inhibitors of poly (ADP-ribose) polymerase to potentiate cytotoxic drugs." Thesis, University of Newcastle Upon Tyne, 1996. http://hdl.handle.net/10443/1025.
Full textAbstract:
The abundant nuclear enzyme poly (ADP-ribose)polymerase (P ARP) catalyses the formation of long homopolymeric chains of ADP-ribose, utilising NAD+ as a substrate, as the immediate cellular response to DNA damage. PARP recognises a damaged section of DNA and initiates polymer synthesis, which is believed to act as a signal to effect the repair of the lesion. A selective, potent PARP inhibitor could block the recognition, and hence repair, of DNA damage induced by cancer chemotherapy. Since increased DNA repair is regarded as a mechanism whereby tumour cells can become resistant to treatment, PARP inhibitors have therapeutic potential as resistance modifying agents. From a study of PARP inhibitors such as 3-hydroxybenzarnide (A), benzimidazole derivatives (B) were proposed as inhibitors of the enzyme, and the synthesis and biological evaluation of a series of such molecules has been achieved. Substituted 2-aryl benzirnidazoles have proved to be highly potent PARP inhibitors (B;R= 4'NO2Ph, IC5o= 59 nM), under a permeabilised cell assay the nitro phenyl derivative (B; R= 4'N02Ph) is the most potent compound reported to date (IC50= 19 nM). 2-Methyl benzirnidazole-4-carboxamide (B; R= Me) has been shown to potentiate the in vitro cytotoxicity of the antitumour agent temozolomide in L1210 cells, and the synthesis of benzimidazole inhibitors suitable for pre-clinical in vivo eluation has also been investigated, This thesis demonstrates that benzimidazole PARP inhibitors have promising potential for clinical development as resistance modifying agents.
14
Lewis, Louisa Joy. "Study of novel dual topoisomerase poisons as potential anti-cancer drugs." Thesis, University of Surrey, 2005. http://epubs.surrey.ac.uk/844572/.
Full textAbstract:
XR5944 and XR11576 are two potent DNA interactive agents, previously shown to be capable of stabilising topoisomerase I and II cleavable complexes in vitro. This thesis investigated the possibility that the mechanism(s) of action of these compounds may be unrelated to that of topo inhibition. These studies made use of a wide range of drug-sensitive and resistant cancer cell lines. It was demonstrated that both XR5944 and XR11576 retain potent cytotoxicity in cancer cell lines presenting with atypical drug resistance to single topoisomerase poisons. XR5944 showed less potency in cell lines expressing ABC-transporter proteins, but this may not be sufficient to compromise the activity of this potent anti-tumour agent in the clinical setting. The mechanism of XR11576 induced cytotoxicity was not affected by any of these transporters and from this and other observations it may possess a different mechanism of action from XR5944. An apoptotic response was observed in XR5944 and XR11576 treated cells. Factors such as Bax and t-Bid were expressed in increasing amounts in response to treatment and implicated the mitochondrial route of apoptosis in these compounds' mechanism of cell kill. Both XR5944 and XR11576 induced appreciable levels of DNA-protein crosslink formation and induced a p53 DNA damage response in drag treated cells. Differences in the timing of onset and extent of DNA damage and p53 induction were noticed between the two compounds. Overall, XR5944 was slower at causing these DNA interactive effects in line with the onset of cytotoxicity. However, this did not appear to pose any particular problems, such as scheduling of dosing, with regard to its in vivo activity, as shown by the work of others. These findings suggest that both XR5944 and XR11576 promote potent cytotoxicity in cancer cell lines showing multiple mechanisms of drug resistance and, therefore, should be of use in the clinic for the treatment of drug resistant tumours. The data presented in this thesis suggest that neither agent exerts its cytotoxicity via a topo directed effect. Furthermore, some of the data generated suggests that these two compounds may differ from each other in their mechanisms of action.
15
Yan, Ruiyang. "Targeted delivery of anti-cancer drugs by MS2 virus-like particles." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/8989/.
Full textAbstract:
Problems associated with poor pharmacokinetics and biodistribution, as well as toxic off-target effects, limit the curative potential of most anti-cancer drugs. This has prompted the development of nanoparticulate drug delivery systems to impart both more favourable pharmacological properties and precise tumour targeting. The vast number of formulations, ranging from fully synthetic delivery systems to ones derived from natural sources, currently undergoing clinical trials or preclinical testing underlines the significance of this field. This project is a proof-of-concept investigation into the feasibility and effectiveness of a novel drug delivery system, based on virus-like particles (VLPs) of the MS2 bacteriophage. Doxorubicin (Dox) and an anti-BCL2 siRNA were used as model drug cargos. They were packaged inside MS2 VLPs either by chemical infusion, or via covalent attachment to an MS2 packaging signal, TR, respectively. An average loading of ~10 molecules of siRNA or ~110 molecules of Dox per VLP was achieved. Packaged cargos remained stably encapsidated; the siRNA was protected from nuclease degradation. VLPs were surface decorated with polyethylene glycol (PEG), and tumour-targeting ligands, human transferrin (Tf) or A9L, an RNA aptamer that targets prostate-specific membrane antigen (PSMA). Extensive PEGylation was achieved (~97% of coat proteins), and each VLP displayed on average ~7 molecules of Tf or ~16 molecules of A9L. PEGylation significantly reduced the non-specific cellular uptake of VLPs, and antibody binding. Further addition of tumour-targeting ligands facilitated the specific delivery of drug cargos to targeted cancer cells in culture, likely via receptor-mediated endocytosis, and induced significant cytotoxicity with an LC50 of ~10 nM for siRNA and ~800 nM for Dox. Importantly, negligible toxic effects were observed in the presence of excess free targeting ligands, or with non-targeted control cell lines. Furthermore, the cellular uptake of VLPs did not appear to induce any off-target effects. MS2 VLPs continue to show promise as a robust, flexible and effective drug delivery system. This project highlights the versatility of VLPs for displaying a range of useful ligands on their surface, as well as packaging various therapeutic cargos, and demonstrated their ability to specifically deliver drugs to targeted cancer cells. Though further studies are required, the work presented here is an important step towards fully realising the potential of this drug delivery system.
16
Pageni, Parasmani. "Synthesis of Ester Derivatives of Resveratrol as Potential Anti-Cancer Drugs." Digital Commons @ East Tennessee State University, 2013. https://dc.etsu.edu/etd/1181.
Full textAbstract:
Resveratrol is a naturally occurring phytoalexin of the stilbene family produced by various plants in response to stress, UV radiation, and fungal attack. It is primarily found in peanuts, berries, grape skin, and red wine. Resveratrol has been found to exhibit anti-cancer, anti-inflammatory, anti-aging, and anti-oxidant properties. Research indicates that diets enriched with resveratrol containing substances result in less incidence of cancer. Unfortunately, the low bioavailability and solubility has been a huge setback for its potential prospects. As a result, efforts have been made to synthesize derivatives of resveratrol with increased solubility and bioavailability. Three triester novel resveratrol derivatives 3, 4’, 5-tri (benzoyloxy) stilbene, 3, 4’, 5-tri (toluyloxy) stilbene and 3, 4’, 5-tri (2”-butenoyloxy) stilbene have been synthesized by esterification process that can further be subjected for biological evaluation. Structures and purities of all newly synthesized derivatives were confirmed by 1H, 13C NMR spectroscopy and infrared spectroscopy.
17
Bannerman-Akwei, Laude. "Synthesis of Marine Chemicals and Derivatives as Potential Anti-Cancer Drugs." Digital Commons @ East Tennessee State University, 2008. https://dc.etsu.edu/etd/1990.
Full textAbstract:
Two natural marine compounds, 3-bromo-4,5-dihydroxybenzaldehyde 2 and 2,3-dibromo-4,5-dihydroxybenzaldehyde 5 together with two novel derivatives, 3-bromo-5-(tert-butyl-dimethyl-silanyloxy)-4-hydroxybenzaldehyde 3 and 1-bromo-2,3-dimethoxy-5-nitrooxy-methylbenzene 9, were synthesized. Compounds 2, 3, and 5 were evaluated for their biological activity towards the inhibition of prostate cancer cell growth using staurosporine a a positive control. All three compounds have shown significant inhibition of prostate cancer cell growth. Compound 9 is yet to be evaluated.
18
Malik, Nazreen. "Development of carbon-ll labelling agents for the radiosynthesis of compounds of clinical interest." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271638.
Full text
19
Mitchell, Ian S. "Synthetic investigations towards rhizoxin." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336923.
Full text
20
Lembicz, Nicola. "The synthesis and biological evaluation of inhibitors of the DNA repair protein O26-alkylguanine-DNA alkyltransferase." Thesis, University of Newcastle Upon Tyne, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362525.
Full text
21
Evans, Delwyn Roger. "Reactions of ruthenium complexes with nucleic acid components." Thesis, University of York, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306345.
Full text
22
Samuels, C. S. "An evaluation of 6-thioguanine derivatives as potential anti-cancer agents." Pretoria : [s.n.], 2008. http://upetd.up.ac.za/thesis/available/etd-11262009-174642/.
Full text
23
SHROFF, PURVI B. "AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF BEXAROTENE." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123813553.
Full text
24
McKay, Judith A. "The expression of xenobiotic metabolising enzymes in human tumours." Thesis, University of Aberdeen, 1996. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU078740.
Full textAbstract:
The cytochromes P450 (CYPs), epoxide hydrolases (EHs) and glutathione S-transferases (GSTs) are three of the major families of enzymes involved in the metabolism of xenobiotics in the human body. Immunohistochemical analysis revealed a high frequency of expression of xenobiotic metabolising enzymes in all tumour types studied, in contrast to corresponding normal tissue which displayed only low levels of expression. Further examination of the CYP1 family was carried out by immunoblot analysis. All breast tumours studied were found to express CYP1B1, and not CYP1A1 or CYP1A2. Moreover, CYP1B1 was identified in a number of kidney tumours but not in corresponding normal kidney, indicating that CYP1B1 may be a tumour-specific form of CYP, RT-PCR, in combination with restriction digestion and DNA sequencing, was used to identify CYP mRNA species present in several tumour types. Although CYP1A1 mRNA was identified in breast carcinomas, CYP1B1 was found to be the most frequently expressed form of the CYP1 family in this tissue. CYP3A mRNA was also displayed by several breast tumours, and demonstrated by sequencing to be CYP3A5. A similar situation to breast tumours was observed in tumours of the gastro-intestinal and urinary tracts, with CYP1B1 being the most frequently expressed form of the CYP1 family, and only a small number of samples displaying evidence of CYP1A mRNA. The effects of the expression of xenobiotic metabolising enzymes in tumours may be complex, and depend upon the relative amounts of active protein present, but it is likely that they will exert an influence on both the development of carcinogenesis and the anti-cancer drug resistance of tumours.
25
Demetci, Demet. "Preparation And Evaluation Of Polymer Based Microcarriers For Hydrophobic Anti-cancer Drugs." Master's thesis, METU, 2007. http://etd.lib.metu.edu.tr/upload/2/12609041/index.pdf.
Full textAbstract:
Chemotherapy is one of the most important treatments for cancer. However, systemic toxicity, drug resistance and unstable kinetics of the drug in the blood are serious problems of chemotherapy. The use of biodegradable polymers for controlled release of anticancer drugs has gained popularity in recent years. Controlled release of drugs from polymeric carriers has some advantages such as improvement in the efficiency of treatment, reduction in systemic toxicity and prevention of the drug resistance that is developed by the cancer cells.
In this study, poly(D,L-lactide-co-glycolide) microparticles were used as carriers for the controlled release of all-trans-Retinoic acid, tamoxifen, tamoxifen citrate and idarubicin. It was aimed to prepare a drug carrier system for controlled release of hydrophobic anticancer drugs.
The empty and drug loaded poly (D,L-lactide-co-glycolide) microparticles were prepared by solvent extraction/evaporation technique with single emulsion (oil/water). Optimized microparticles were characterized by using inverted light microscopy and scanning electron microscopy to examine their morphology and sizes. Drug content of microparticles and the amount of released drug were determined spectrophotometrically. In vitro toxicity of the microparticles on MCF-7 human breast cancer cells was investigated.
It was revealed that the microparticles were smooth and spherical in shape. Their sizes differed in the range of 2-20 µm. atRA-loaded microparticles showed approximately 90% encapsulation efficiency and it was confirmed that changing in drug/polymer ratio affected the extend of drug content. Increase in drug content caused a slower release pattern. Moreover, although the empty microparticles caused some toxicity, atRA-loaded PLGA microparticles showed slight cell growth inhibition.
26
Gitari, Patricia Wanjiru. "Synthesis and testing of palladium and platinum phosphine complexes with potential mitochondrial targeting anti-cancer properties." Pretoria : [s.n.], 2009. http://upetd.up.ac.za/thesis/available/etd-09232009-171302/.
Full text
27
Walker, Alex J. "Anti-cancer actions in commonly used drugs : epidemiology led by laboratory science." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12205/.
Full textAbstract:
Despite considerable research on cancer treatments and preventatives, poor outcomes in cancer patients are common. The vital search for effective cancer drugs often begins in the laboratory, where unfortunately the effects of a drug in humans cannot be perfectly modelled. Epidemiology can play a vital role in determining the real world efficacy of a drug currently used for other purposes before clinical trials begin. This thesis therefore used primarily laboratory evidence to identify potential anti-cancer uses for existing common drugs. The drugs and cancers studied were; tricyclic antidepressants and both incidence and survival in a number of cancer types, particularly glioma; aspirin and colorectal cancer survival; and angiotensin converting enzyme (ACE) inhibitors and hepatocellular carcinoma (HCC) incidence. A series of studies using The General Practice Research Database as a data source assessed any potential associations: A case-control study for tricyclic antidepressant use and cancer incidence; cohort studies to examine mortality in colorectal cancer and glioma in relation to tricyclic use, and for colorectal cancer mortality in aspirin users; and a case-control study in relation to ACE inhibitor use and HCC. A strong, cancer type specific, dose and time dependant protective effect was found for the incidence of glioma and colorectal cancer. This led to a further study examining mortality for these cancer types in tricyclic users. While no significant protective effects in all-cause mortality of tricyclic users were found, a larger study could still find such an effect in glioma. For aspirin and colorectal cancer mortality, a small but significant reduction in mortality was observed, though these effects were not entirely consistent throughout the study. There were no significant associations found between ACE inhibitors and HCC. These findings contribute to the knowledge of the anti-cancer effectiveness of these drugs, and may assist in designing future clinical studies.
28
Smith, Victoria. "Mechanisms of resistance to novel cell signalling inhibitor based anti-cancer drugs." Thesis, Institute of Cancer Research (University Of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271024.
Full text
29
Elliott, Christopher S. "The Chemoprevention of Lung Cancer Using Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1041537546.
Full text
30
Kroll, Sebastian Herbert Benjamin. "Towards the synthesis of selective CDK7 inhibitors as potential anti-cancer drugs." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/11657.
Full textAbstract:
Cyclin-dependent kinase 7 (CDK7) exhibits an interesting target for an anti-cancer therapy approach. CDK7’s triple role in phosphorylation (cell cycle, transcription, estrogen receptor (ER)) in cell regulation makes this kinase interesting. Phosphorylation of cell cycle CDK’s via its CAK-complex, of Ser-5 in RNA-PolII as part of the TFIIH-complex and phosphorylation of Ser-118 in ER all show the importance of this enzyme. Given that CDKs are over-expressed in many cancers, selective inhibition of CDK7 should result in cell cycle arrest and apoptosis predominately in tumour cells. Previously, BS-181 (Figure 0.1) has been reported as the first CDK7 selective inhibitor, which displayed a good in vitro and in vivo profile.1 Based on this initial lead compound, a library of rational-designed analogues was synthesised. Much of this library was based on a computer-aided-drug-design (CADD) approach by docking, which gave valuable insights in possible binding modes and helped to focus targeting the whole active site. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 0.1: BS-181 and new analogues. Several of these novel inhibitors showed excellent selectivity versus CDK2 in particular, and potency against CDK7 in the 30 – 60 nM range for their IC50-values. Cellular assays confirmed the growth inhibitory properties of these new compounds, with GI50-values in the low μM range. This work also demonstrates what functional groups were tolerated in the 3-,5- and 7-position.
31
Batubara, Afnan. "Distribution of anti-cancer drugs in solid tumours studied by MALDI-MSI." Thesis, Sheffield Hallam University, 2015. http://shura.shu.ac.uk/20623/.
Full textAbstract:
Vascular disrupting agents (VDAs) have been used in treatment of many cancers. 5,6 -dimethylxanthenone-4-acetic acid (DMXAA) is a low molecular weight drug of the flavonoid group which has an anti-vascular effect in tumours causing endothelial cell apoptosis and activation of cytokines. A study employing matrix assisted laser desorption ionisation-mass spectrometry (MALDI-MS) imaging to examine LS174T colorectal adenocarcinoma xenografts following administration of DMXAA has been conducted to study the distribution of anti-cancer drugs and to explore markers of efficacy and resistance. Initial work established the limit of detection /quantitation of DMXAA in tissue. The drug limit of detection (LoD) is determined as 10 ng/ml and the drug lower limit of quantitation (LLoQ) is 45 ng/ml. MALDI images were recorded from LS174T colorectal adenocarcinoma xenografts removed from immunodeficient mice following treatment with with 27.5 mg/kg DMXAA. These indicated that the drug was distributed mainly in the centre of tumour 4h post-treatment, whilst it was distributed around the periphery 24h posttreatment. A study of lipid expression in treated tumors demonstrated that washing tissue sections with 150 mM ammonium acetate solution (NH[4]AC) improved the intensity of lipids signals in both negative and positive ion mode. These images also indicated that sphingomyelins (SM) and phosphatidylcholines (PC) lipid species were highly expressed in cancerous tissue. A thin layer chromatography-matrix assisted laser desorption ionisation-mass spectrometry (TLC-MALDI-MS) experiment has been carried out for the analysis of phospholipids extracted from the treated xenograft tumours. The lipid extracts were separated into 6 spots on the TLC plate. These were identified as lysophosphatidylcholines (LPC), sphingomyelins (SM), phosphatidylcholines (PC) and phosphatidylethanolamines (PE). The TLC-MALDI-MS data indicated that LPC were highly expressed in the 4h and 24h post-treated tumour samples compared to the control. An increase in expression of LPC lipids in solid tumours treated with DMXAA has been demonstrated and shown to be localised in the central area of the tumour. Mass spectrometry imaging was also used to characterise proteins and peptide signal in tumours after treatment with DMXAA. Histone H2A peaks at 944 m/z were highly expressed in the region of the tumours. In addition, a characteristic increase in the Hb beta chain at 1274.74 m/z in the 24h post-treated tumour has been seen. The data obtained from PCA has shown that the levels of certain proteins changed over the different tumour time point.
32
Calvete, Joanne Amanda. "Pre-clinical studies with the novel colorectal cancer targeted immunotoxin, ICI D0490." Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336268.
Full text
33
Isaacs, Richard John. "Transcriptional regulation of human topoisomerase II#alpha#." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320230.
Full text
34
COPPOLA, CONCETTA. "Caratterizzazione di farmaci per la cura del cancro, di malattie neurodegenerative e infiammatorie per mezzo della tecnica EPR." Doctoral thesis, Urbino, 2015. http://hdl.handle.net/11576/2628891.
Full text
35
Chew, Angela Christine. "The anti-proliferative effects of thiazolidinediones and non-steriodal anti-inflammatory drugs on androgen-independent prostate cancer." University of Western Australia. School of Medicine and Pharmacology, 2009. http://theses.library.uwa.edu.au/adt-WU2009.0200.
Full textAbstract:
[Truncated abstract] In recent years a better understanding of the biology of PPAR , a nuclear transcription factor, has emerged, leading to a resurgence in targeting PPAR for chemotherapy. The family of synthetic PPAR agonists, the thiazolidinediones (TZDs), and non-steroidal anti-inflammatory drugs (NSAIDs) have been implicated in the inhibition of cell proliferation, apoptosis and cell cycle arrest of androgen-sensitive (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cells generating much interest in their use for potential curative cancer therapies. In light of the potential use of TZDs and NSAIDs in prostate cancer prevention and their ability to induce inhibitory effects in vitro and in vivo, the first aim of this project was to undertake a comprehensive study of the effects of ciglitazone (TZD) and indomethacin (NSAID) on the androgen-independent prostate cancer cell line DU145, using standardised concentrations and time-points to compare the effects of TZDs and NSAIDs on cell proliferation, cell cycle and apoptosis. Treating the cells with either 10 µM ciglitazone or 10 µM indomethacin resulted in a time-dependent decrease in DU145 cell proliferation. The anti-proliferative effects were found to be in-part attributed to the slowing of cell progression through the G1/S-phase checkpoint of the cell cycle, and in the case of ciglitazone, apoptosis also played a role in its anti-proliferative effects in this cell line. Interestingly, although indomethacin failed to induce apoptosis, its antiproliferative effects were more potent than ciglitazone. The second aim of this project was to further investigate the underlying mechanisms responsible for the anti-proliferative effects of ciglitazone and indomethacin by evaluating their ability to modulate PPAR mRNA and protein expression, and to induce PPAR transcriptional activity. ... In addition, ligandinduced regulation of secreted frizzled related protein 4 (sFRP4) expression, a Wnt/ - catenin antagonists, was investigated. It was demonstrated that both ciglitazone and indomethacin attenuated Wnt/ -catenin signalling via the down-regulation of total - catenin levels within the cells, inhibition or slowing of the translocation of cytoplasmic -catenin into the nucleus and inhibition of cyclinD1 expression An inverse relationship between PPAR and -catenin protein levels was also detected, suggesting that PPAR may directly bind to -catenin itself. sFRP4 expression was transiently upregulated by ciglitazone and indomethacin-treatment, suggesting that the antiproliferative effects of the ligands may be mediated in part through regulation of sFRP4 mRNA and protein levels. In summary, the anti-proliferative effects of ciglitazone and indomethacin on the androgen-independent prostate cancer cell line, DU145, described in this thesis are progressive steps in characterising the role of PPAR in prostate cancer cell proliferation. The identification of indomethacin as a more potent PPAR agonist than ciglitazone represents a novel target for the development of preventative strategies for advanced disease, and the relationship between PPAR and the Wnt/ -catenin signalling pathway provide an insight into the mechanisms involved in the anti-proliferative effects of ciglitazone and indomethacin. Further studies into this relationship would advance help identify novel preventative and curative therapeutic strategies for advanced prostate cancer.
36
朱耿慧 and Genghui Zhu. "Nonsteroidal antiinflammatory drugs and apoptosis of human gastric epithelial cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B31239845.
Full text
37
Feng, Ye. "DEVELOPMENT OF QUANTITATIVE BIOANALYTICAL METHODS FOR THE PHARMACOLOGICAL STUDIES OF ANTI-CANCER DRUGS." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1392249778.
Full text
38
Collins, James Charles. "Inhibitors of Cdc25 phosphatases : potential anti-cancer drugs and tools for chemical genetics." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/11189.
Full textAbstract:
Cdc25 phosphatases play a crucial role in the regulation of the cell cycle, and overexpression of the three known isoforms has been directly correlated with poor cancer prognosis. Inhibition of this enzyme could prove to be an effective therapeutic strategy, but the most potent reported inhibitors lack specificity and an appropriate mechanism of action. Furthermore, more basic research is needed into the structure and precise cellular function of the different cdc25 isoforms. Following a literature survey, panels of novel inhibitors modelled on the natural product dysidiolide and reported quinonoid compounds were synthesised. Initial phosphatase assay results with cdc25A discouraged any further synthesis of related inhibitors. The untagged catalytic domain of each isoform was prepared, expressed and purified to carry out NMR structural studies. However, preliminary spectra showed a high degree of conformational flexibility that made further analysis prohibitively difficult. Extensive screening of crystallisation conditions also did not prove successful. As an alternative strategy, a ligand-based virtual screening approach using an optimised selection of reported inhibitors resulted in discovery of diarylthiazoles as novel, potent and drug-like inhibitors of cdc25 and the related phosphatase VHR. Some of these compounds also demonstrated potent anti-proliferative activity against a panel of cell lines. Parallel synthesis of a wide range of diarylthiazole analogues using a regioselective, sequential Pd-coupling approach proved moderately successful, identifying promising novel inhibitors for further development, although without significantly increasing the binding affinity. Screening of a wide range of commercially-available compounds chosen by a substructure analysis identified further promising inhibitors, which compare favourably with the best literature compounds. Attempts to develop novel methodology for the rapid and divergent synthesis of aminothiazoles ultimately proved unsuccessful with respect to various approaches to the difficult C-N bond formation, but simple conditions were found for the synthesis and Suzuki coupling of a highly electron-rich aminothiazole C4-triflate.
39
Chetcuti, Anthony Raphael Michael. "Role of Transferrin Binding in the Biological Activity of Ruthenium Anti-Cancer Drugs." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18987.
Full textAbstract:
Ruthenium anti-cancer drugs are extensively studied as an alternative to platinum drugs that are widely used in the clinic, but suffer from major side effects and the development of resistance. One such drug, indazolium trans-tetrachloridobis(1H-indazole)ruthenate(III) (KP1019) has undergone Phase I and early Phase II clinical trials. Transferrin (Tf) is the main transport protein responsible for the delivery of essential Fe(III) from blood to the cells. Various researches have hypothesised that Tf can also mediate the transport of non-biological metals (e.g., Ru(III) from KP1019) into cells, bound to either to Fe(III) binding sites or to the side chains of Tf. This mechanism can potentially lead to selective anti-cancer activity of Ru(III)-based drugs due to higher metabolic demands for Fe(III) in cancer vs. normal cells. In this work, the hypothesis of Tf-mediated Ru transport was tested using biolayer interferometry (BLI), UV-Vis absorption spectroscopy and particle size measurements. The role of Tf in the biological activity of KP1019 was further investigated by studies on the uptake of Ru(III)-Tf and Fe(III)-Tf adducts by HepG2 (human hepatoma) liver cancer cells, using inductively coupled plasma mass spectrometry (ICP-MS), atomic absorption spectroscopy (AAS) and Bradford protein assays. Experimental results indicated that: i) the initial step in the cytotoxicity of KP1019 involved mainly passive diffusion of the drug into the cell, and formation of Ru(III)-Tf adducts inhibited rather than enhanced the cellular uptake of KP1019; ii) binding of KP1019 to the Fe(III) binding sites of Tf severely disrupted Tf binding to Tf receptors on the cell surface, which prevented cellular uptake of Ru(III); and iii) binding of Ru(III) to Tf was efficiently prevented by the presence of physiological concentrations of human serum albumin. In summary, these results provided strong evidence to discount the postulate of Tf-mediated transport of Ru anti-cancer drugs into cells.
40
Adiwidjaja, Jeffry. "Understanding interindividual variability in response to anti-cancer drugs using modelling and simulation." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23217.
Full textAbstract:
Long-term use of imatinib in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) is effective. Imatinib is given orally at a fixed daily dosing regimen (400 – 800 mg/day) in adult patients, despite evidence of large interindividual variability in systemic exposure. As the relationship between imatinib exposure (as trough concentrations or Css,min) and clinical outcomes (efficacy and safety) has been established, understanding the mechanisms underlying pharmacokinetic variability would be of clinical importance for dose optimisation in individual patients. Imatinib is a substrate for both cytochrome P450 (CYP)3A4 and CYP2C8 enzymes, and so is liable to interactions with other drugs or natural products. Bosutinib, another kinase inhibitor approved for frontline treatment of Ph+ CML, is almost exclusively metabolised by CYP3A4, posing a risk for drug interactions with CYP3A modulators. There is also a potential for inter-ethnic and age-related differences in imatinib pharmacokinetics due to variability in body and liver sizes and activity of CYP enzymes. The potential interactions between imatinib and coadministered drugs in children with CML also remains largely unexplored. Clearly, a quantitative framework, such as the physiologically-based pharmacokinetic (PBPK) modelling approach, would be beneficial to understand interindividual variability in response to imatinib and bosutinib and to predict drug interactions with these drugs. This study aimed to investigate potential sources of interindividual variability in pharmacokinetics of imatinib and bosutinib using a PBPK modelling approach. A PBPK model for imatinib in adult populations was developed and extrapolated to paediatrics. The PBPK model was able to describe imatinib pharmacokinetics in both populations. The PBPK simulation suggests that the optimal dosing regimen range for imatinib is 230 – 340 mg/m2/day in paediatrics, which is supported by the recommended initial dose for treatment of childhood CML. The simulations also highlighted that children and adults being treated with imatinib have similar vulnerability to CYP modulations. The PBPK model of imatinib was further extrapolated to describe the pharmacokinetics of imatinib across different ethnic groups and dosing regimens. The PBPK model described imatinib pharmacokinetics in patients from different geographical ancestries and demonstrated excellent predictive performance in simulating the attained Css,min following a range of dosing regimens. PBPK simulation suggested a similar dose of imatinib (400 – 600 mg/day) to achieve the targeted Css,min (1,000 – 3,200 ng/mL) in populations of European, Japanese and Chinese ancestry. The simulations indicated that patients of African ancestry may benefit from a higher initial dose of imatinib (600 – 800 mg/day) to achieve imatinib target concentrations, due to a higher apparent clearance (CL/F) of imatinib compared to other ethnic groups. People with CML and receiving treatment with kinase inhibitors are known to concomitantly use natural products, including St John’s wort (SJW), Schisandra sphenanthera and curcumin, with a purported aim to help manage adverse effects and comorbidities. A PBPK model was developed of hyperforin, the constituent of SJW responsible for interactions, accounting for the induction of CYP3A, CYP2C9 and CYP2C19 with a predictive capability for the interactions of SJW with a range of CYP substrates. Simulations revealed that induction of intestinal CYP enzymes by hyperforin was more pronounced than the corresponding increase in liver CYP activity (15.5- vs 1.1-fold, respectively at a hyperforin dose of 45 mg/day). Since imatinib undergoes little to no metabolism in the enterocytes, induction of CYP3A by hyperforin is unlikely to affect steady-state CL/F of imatinib. PBPK models of Schisandra lignans (schisantherin A, schisandrin A and schisandrol B) were developed and verified using clinical pharmacokinetic and drug interaction data. The verified PBPK models were able to describe the increase of systemic exposure of midazolam and tacrolimus due to coadministration of S. sphenanthera, consistent with the reported changes in the corresponding clinical interaction study (AUC ratio of 2.0 vs 2.1 and 2.4 vs 2.1, respectively). Potential interactions with imatinib and bosutinib were evaluated and predicted utilising both an in vitro interaction study and a PBPK modelling approach. Interaction between imatinib and Schisandra lignans was unlikely to be of clinical importance. Conversely, S. sphenanthera, at a clinically-relevant dose, results in a predicted three-fold increase in bosutinib systemic exposure. Curcumin demonstrated potent reversible inhibition of CYP3A4-mediated N-demethylation of imatinib and bosutinib and CYP2C8-mediated metabolism of imatinib with inhibitory constants (ki,u) of ≤ 1.5 µmol.L-1. Curcumin glucuronide, a major circulating metabolite of curcumin, also inhibited both CYP enzymes in vitro, albeit to a lesser extent than that of curcumin. PBPK model simulations predicted that, at recommended dosing regimens of curcumin formulated in a solid lipid nanoparticles delivery system, coadministration would result in an increase in systemic exposures of imatinib and bosutinib of up to only 10%. This is an example of potent in vitro CYP inhibition that is unlikely to manifest clinically due to poor bioavailability of the perpetrator compounds. PBPK modelling and simulation approach is an excellent tool to explore potential sources of interindividual variability in pharmacokinetics, including age, ethnicity and drug interactions. Ultimately, understanding the potential sources of pharmacokinetic variability can help guide optimal dosing regimens of imatinib and bosutinib for individual patients to achieve optimal clinical outcomes.
41
Adamska, Aleksandra. "ABC transporters and G protein-coupled receptors: perspectives for novel anti-cancer drugs." Thesis, Curtin University, 2019. http://hdl.handle.net/20.500.11937/77548.
Full textAbstract:
Pancreatic Ductal Adenocarcinoma (PDAC) is a very aggressive disease with high mortality rates and lacking effective therapeutic approach. Therefore, it is pivotal to develop novel treatments to improve the grim prognosis of patients. In my PhD project, I demonstrated the existence of an ABCC3-LPI-GPR55 loop in PDAC which activation boosts PDAC progression. Importantly, the pharmacological potential of this loop was demonstrated both in vitro and in vivo PDAC models paving a way to clinical trials.
42
Chamberlain, Charlotte Anne. "Access to non-curative anti-cancer therapies on the NHS : the role of the Cancer Drugs Fund." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.720860.
Full text
43
Gu, Qing, and 谷青. "Helicobacter pylori and non-steroidal anti-inflammatory drugs in gastric carcinogenesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36589718.
Full text
44
Tripathi, Ashutosh. "DEVELOPMENT OF HINT BASED COMPUTATIONAL TOOLS FOR DRUG DESIGN: APPLICATIONS IN THE DESIGN AND DEVELOPMENT OF NOVEL ANTI-CANCER AGENTS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1866.
Full textAbstract:
The overall aim of the research is to develop a computational platform based on HINT paradigm for manipulating, predicting and analyzing biomacromolecular-ligand structure. A second synergistic goal is to apply the above methodology to design novel and potent anti-cancer agents. The crucial role of the microtubule in cell division has identified tubulin as an interesting target for the development of therapeutics for cancer. Pyrrole-containing molecules derived from nature have proven to be particularly useful as lead compounds for drug development. We have designed and developed a series of substituted pyrroles that inhibit growth and promote death of breast tumor cells at nM and μM concentrations in human breast tumor cell lines. In another project, stilbene analogs were designed and developed as microtubule depolymerizing agents that showed anti-leukemic activity. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of tubulin inhibitors that bind at the αβ-tubulin colchicine site. These studies coupled with HINT interaction analyses were able to describe the complex structure and the binding modes of inhibitors. Qualitative analyses of the results showed general agreement with the experimental in vitro biological activity for these derivatives. Consequently, we have been designing new analogs that can be synthesized and tested; we believe that these molecules will be highly selective against cancer cells with minimal toxicity to the host tissue. Another goal of our research is to develop computational tools for drug design. The development and implementation of a novel cavity detection algorithm is also reported and discussed. The algorithm named VICE (Vectorial Identification of Cavity Extents) utilizes HINT toolkit functions to identify and delineate a binding pocket in a protein. The program is based on geometric criteria and applies simple integer grid maps to delineate binding sites. The algorithm was extensively tested on a diverse set of proteins and detects binding pockets of different shapes and sizes. The study also implemented the computational titration algorithm to understand the complexity of ligand binding and protonation state in the active site of HIV-1 protease. The Computational titration algorithm is a powerful tool for understanding ligand binding in a complex biochemical environment and allows generating hypothesis on the best model for binding.
45
Angell, Johanna Elizabeth. "Use of Bioluminescent Bacterial Biosensors to Study the Intracellular Metabolism of Anti-Cancer Drugs." Thesis, University of the West of England, Bristol, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.524687.
Full text
46
Tian, Xuefei. "Modulation of the conformaiton [sic] and function of membrane-bound anti-apoptotic Bcl-2 by potential anti-cancer drugs." Oklahoma City : [s.n.], 2008.
Find full text
47
Wong, Chun-yu Benjamin. "Role of Helicobacter pylori and non-steroidal anti-inflammatory drugs in prevention of gastric cancer." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31685493.
Full text
48
Wong, Chun-yu Benjamin, and 王振宇. "Role of Helicobacter pylori and non-steroidal anti-inflammatory drugs in prevention of gastric cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31685493.
Full text
49
JUNIOR, ANILTON COELHO COSTA. "DETERMINATION OF PLATINUM DERIVED FROM ANTI-CANCER DRUGS IN URINE SAMPLES BY ATOMIC ABSORPTION SPECTROMETRY." PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO, 2007. http://www.maxwell.vrac.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=11022@1.
Full textAbstract:
FUNDAÇÃO DE APOIO À PESQUISA DO ESTADO DO RIO DE JANEIROFINANCIADORA DE ESTUDOS E PROJETOS
Devido à sua capacidade de inibição do processo de divisão celular, complexos de platina têm sido empregados na quimioterapia do câncer desde o final da década de 60, sendo a cisplatina e a carboplatina as formas mais utilizadas. Estudos farmacocinéticos e a estimativa da quantidade de platina acumulada no organismo durante o tratamento quimioterápico ou devido à exposição ao metal têm sido alvo de grande interesse. Logo, são necessários métodos analíticos adequados para o monitoramento de platina em amostras clínicas, apropriados para essas diferentes substâncias. No presente trabalho, foram desenvolvidos procedimentos analíticos rápidos, simples e exatos para determinação direta de platina, na forma de cisplatina e carboplatina, em urina humana, utilizando a espectrometria atômica. No caso da absorção atômica em forno de grafite, o programa de temperatura, o volume de amostra e a concentração do diluente (HNO3) foram definidos por um planejamento composto central. Nas condições otimizadas, os resultados obtidos pelo procedimento proposto não apresentaram diferenças estatisticamente significativas daqueles obtidos por procedimentos comparativos independentes, na análise de amostras de urina de paciente submetido ao tratamento com cisplatina. A calibração foi realizada por adição de analito, com PtCl2. Com a adição de NaCl ao meio diluente, os efeitos multiplicativos de matriz puderam ser contornados, permitindo a calibração externa com soluções de calibração preparadas no mesmo meio que o branco, utilizando sais inorgânicos de platina. Melhor sensibilidade também foi obtida, e recuperações de 98±4% foram observadas para os vários níveis de concentração estudados, assim como coeficientes de variação de 1 a 10%, tanto para a cis como para a carboplatina. O limite de detecção (n=10, k=3) foi de 4 (mi)g L-1 de Pt na amostra original. A espectrometria de absorção atômica com fonte contínua de alta resolução na chama (HR-CS F AAS) também foi estudada. As condições da chama foram definidas por um planejamento multivariado D-optimal, tomando-se como resposta a soma dos coeficientes angulares das curvas de adição de analito em três urinas diferentes, assim como o desvio padrão relativo dessas inclinações. O limite de detecção foi de 55 Og L-1 (n=10, k=3), na amostra original, em Pt, cerca de uma ordem de grandeza melhor do que aquele obtido utilizando-se um equipamento de fonte de linhas. Calibração externa, com soluções de calibração em urina livre de Pt, utilizando sal inorgânico de platina (PtCl2), foi possível, e os resultados obtidos por HR-CS F AAS não se mostraram significativamente diferentes daqueles encontrados por procedimentos comparativos independentes.
Platinum coordination compounds have been used in cancer chemotherapy since the late 1960s. Cisplatin and carboplatin are the most common platinum based drugs used in cancer treatment. Pharmacokinetics investigations, the determination of the body burden during the treatment as well as the baseline levels of platinum in humans has attracted great interest. Thus, accurate analytical methods for fast and easy platinum monitoring in clinical samples are necessary. In the present work, atomic spectrometric methods for the direct determination of platinum as cisplatin and carboplatin in human urine were investigated. In relation to Graphite Furnace Atomic Absorption Spectrometry the optimum temperature program, sample volume and diluent concentration were defined by a central composite design optimization. Analyte addition with PtCl2 was used for calibration, and no statistically significant difference was observed between the results obtained by the proposed and comparative procedures in the analysis of a set of urine samples. Multiplicative matrix effects were overcome by adding NaCl to the diluent solution. External calibration with PtCl2 in blank matched medium was then possible. The recoveries were 100±1%, and the coefficient of variation ranged from 1 to 10%. The limit of detection (LOD) was 4 ug L-1 of Pt in the original urine sample. High resolution continuous source flame atomic absorption spectrometry was also investigated. The flame conditions were optimized by a multivariate D-optimal design, taking as response the sum of the analyte addition calibration slopes and their standard deviation. The LOD was 55 Og L-1 (n=10, k=3), in the original sample. Matrix matched external calibration with PtCl2, was possible, and the results obtained by the proposed procedure were also in good agreement with those obtained by independent comparative procedures.
50
Gupta, Nishi. "The evaluation of positron emission tomography to assess pharmacodynamics and pharmacokinetics of anti cancer drugs." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/40004.
Full textAbstract:
Positron emission tomography (PET) is a non-invasive imaging technique that is emerging as a useful tool in the field of cancer medicine particularly in drug development. The purpose of this thesis has been to perform clinical studies using two different radiotracers, 5-[^V]fIuorouracil (5-['^F]FU) and 2-[''C]thymidine, to assess pharmacokinetic and pharmacodynamic parameters respectively, which were derived from PET imaging and to establish the contribution that PET can add to drug development, in vivo, in man. Aims: 1) Quantify the pharmacodynamic effects of cytotoxic agents in tumour and normal tissue using 2-["C]thymidine 2) Measure changes in tumour and normal tissue pharmacokinetics of 5-Fluorouracil in response to the modulating agents carbogen and nicotinamide or interferon 3) Assessment of blood flow change in tumour and normal tissue to carbogen and nicotinamide or interferon 4) Interpretation of PET data using novel analysis methods with modified Patlak and spectral analysis Methods: In the 5-['^]FU study, patients with metastatic gastrointestinal cancer underwent PET scanning at the start of 2 separate chemotherapy cycles. The 2nd scan was performed after the administration of carbogen and nicotinamide or interferon. In the 2-["C]thymidine study patients receiving chemotherapy were scanned before commencing chemotherapy, and 1 week after the 3''' cycle of chemotherapy. Patients also had conventional imaging before the start of and after 3 cycles of treatment. Findings: After carbogen and nicotinamide administration, 5-['^]FU uptake was increased in tumour, but not in normal tissue. Regional perfusion was elevated in tumours but decreased in kidneys after carbogen and nicotinamide. After interferon administration, there was an increase in 5-['^]FU retention in tumours, but no increase in uptake. Regional perfusion in tumour and normal tissue was unaltered by interferon. Retention of 2-["C]thymidine decreased in tumour in keeping with the results of conventional radiology, suggesting a pathological response, assessed in vivo, to chemotherapy.