Platinum compounds are widely used drugs in cancer treatments. Although DNA is the biological target, reaction of platinum compounds with proteins is also potentially significant. Our objective is to study the effects of leaving ligands on the relative reactivity between 5'-GMP (guanosine 5' phosphate), a key DNA target, and N-Acetyl - L-Methionine (N-AcMet), a key protein target. We have used NMR spectroscopy to monitor reactions with N-AcMet and 5'-GMP added to a platinum complex to see which products are formed preferentially. Previous research showed that both a non-bulky complex such as [Pt(en)(D2O)2]2+ [en=ethylenediamine], and a bulky complex such as [Pt(Me4en)(D2O)2]2+ [Me4en= N, N, N', N'-tetramethylethylenediamine] react more quickly with 5'-GMP than with N-AcMet. To improve the activity of platinum compounds in our current research, oxalates as leaving ligands are used. The results suggest that [Pt(en)(Ox)] [Ox= oxalate] reacts faster with N-AcMet than with 5'-GMP. Also, [Pt(Me4en)(Ox)] reacts slowly with 5'-GMP without N-AcMet and the reaction favors N-AcMet when both ligands are added simultaneously. Interestingly, the formation of the sulfur-oxygen chelate is slow enough to be observable in the oxalate reaction; but the mono product is not independently observed in the dinitrate complex.

This thesis describes a three year study which explored perceptions and experiences of being involved in self care and perceptions of control and self-efficacy over time amongst patients receiving a six month course of chemotherapy treatment for colorectal cancer. The study was underpinned by Leventhal’s Self Regulation Model and aimed to explore how patients undergoing chemotherapy for colorectal cancer perceived the meaning of self care, what they did as part of their self care in managing the effects of their treatment and whether this changed between the beginning and end of their six month course of chemotherapy. The study also set out to explore the relationship between patients’ perceptions of control and self efficacy and their involvement in self care. The study adopted a patient focussed, mixed method, longitudinal approach for complementarity and expansion purposes in which the qualitative findings formed the focus of the investigation, supplemented by the quantitative findings. This was important to provide a greater breadth and range to the study and to obtain a realistic understanding of patients’ perceptions and experiences of being involved in self care during their six month course of chemotherapy treatment and the influence of their perceptions of control and self efficacy on their involvement in self care. Thirty one patients participated in the study and data were collected using qualitative semi structured interviews (with a subsample of patients who participated in the study) and quantitative questionnaires (Illness Perception Questionnaire-revised and the Strategies Used by People to Promote Health) and prospective self care diaries with the full study sample. Data were collected at several time points over the course of patients’ chemotherapy treatment (beginning, middle and end of treatment) and were analysed and integrated in accordance with Tashakkori and Teddlie (1998)’s guidance for integrating qualitative and quantitative findings in a mixed methods study. The study findings revealed that the use of a mixed method, longitudinal study design was a valuable approach for understanding patients’ involvement in self care during chemotherapy for colorectal cancer and the influence of factors, such as their perceptions of control, on their subsequent involvement in their self care. In particular, the principal findings suggested that self care held a range of meanings to the patients in this study. Principally, patients’ self care consisted of two components; physical self care, carried out to manage the physical impact of undergoing treatment, and emotional self care, carried out to manage their emotional response to being diagnosed with, and undergoing treatment for, cancer. The findings suggested that there was no association between patients’ perceptions of control and the degree of self care that they carried out identified in the quantitative analysis. However, in the qualitative analysis, it was revealed that patients’ perceptions of control were likely to influence their attitudes towards their active involvement in self care and the importance with which they viewed this role. In particular, patients who considered themselves to have a high degree of control during their treatment were more likely to believe that they could limit the impact of the treatment through their own actions, that being actively involved in their self care was important and were interested in taking on this role, and that they would use a greater range of self care strategies in helping to manage the impact of their treatment. Conversely patients who considered themselves to have a lower degree of control during their treatment were less likely to believe that they could limit the impact of the treatment through their own actions, that their active involvement in self care was important and were less likely to expect to take on an active role, preferring to leave the management of treatment-related effects to health professionals, whom they regarded as being the “experts”. The findings from this study have implications for nursing practice because they reinforce the importance of the listening to the patient’s experience and how this approach can contribute to a fuller and more accurate understanding of how patients become involved in their self care and the factors that influence this. This is important so that nurses can provide holistic care, tailored to meet their patients’ self care needs and preferences, and to encourage partnership working between patients, nurses, allied health professionals and other agencies in promoting involvement in self care. The findings also have implications for theories relating to self care in emphasising the importance of patient centred models of care and for Leventhal’s Self Regulation Model in adding further support for the components of the model yet also offering a greater understanding of how the model fits with patients’ emotional responses to the effects of illness and its’ treatments. Finally, the study findings have implications for future research, calling for further research to focus on the meaning of constructs such as self care and control from the patients’ perspective and to further explore the use of the mixed methodology in researching and understanding patients’ involvement in self care and the factors that influence this.

Purpose: Control of micrometastatic ovarian cancer in the peritoneal cavity remains a major objective in post-surgical treatment. The purpose of this project was to investigate the efficacy and toxicity of targeted alpha therapy (TAT) for ovarian cancer in vitro and in vivo in animal models and to select the optimal targeting vector for an ovarian cancer clinical trial. Animal models of ovarian, breast and prostate cancer were developed and for further TAT; a phase I melanoma clinical trial was supported, paving the way for an ovarian cancer clinical trial. Methods: The expression of the turnor-associated antigens (Her2, MUC1, uPAfuPAR) on cancer cell line, animal model xenografts and human ovarian cancer tissue was tested by immunostaining. MTS and TUNEL assays were used to evaluate cell killing of alpha conjugates in monolayer and spheroids. Toxicity and maximum tolerance doses for different vectors were tested and determined in vivo. Pharmacokinetics was studied for different time points and different parameters. The antiproliferative effect of 213Bi-C595 and 213Bi-PAI2 was tested at 9 days post-peritoneal cell inoculation of the ovarian cancer cell line OVCAR3. The treatment efficacy of 213Bi-Herceptin was tested at a 2 days post-subcutaneous breast cancer cell BT474 inoculation. Mice were injected (i.p) with various concentrations of alpha conjugates (AC). Changes in cancer progression were assessed by girth size and tumor size. Results: uPA/uPAR and MUCI are expressed on ovarian cancer cell lines and more than 45% ovarian cancer tissue, while HER2 was only positive in one cell line and was positive in less than 15% of ovarian cancer tissues. The ACs can target and kill cancer cells in vitro in a dose dependent fashion. TUNEL positive cells were found after incubation with the different ACs. PAI2 and C595 vectors were selected for in vivo ascites model study of OVCARJ cell with high expression. Delayed and acute toxicity in animal models showed that radiation nephropathy was the cause of body weight loss. Biodistribution studies showed that kidney was the major uptake organ. L-lysine can reduce kidney uptake for 213Bi-PAI2, but no significant differences were found. A single ip injection of 213Bi-C595 or 213Bi-PAI2 can inhibit ascites growth, whereas, 213Bi-Herceptin can inhibit breast cancer growth in a nude mice model. Conclusion: 213Bi labelled targeting vectors can specifically target ovarian cancer cells in vitro and inhibit tumor growth in vivo. These ACs may be useful agents for the treatment of ovarian cancer at the minimum residual disease stage.

[Truncated abstract] Clinical and pathological predictors of survival for stage II and III colon cancer patients treated with or without chemotherapy: a population-based study. Aim: Using a population-based cohort of colorectal cancer (CRC), the major aims of this study were to: 1. Identify clinico-pathological markers that can be used to define a subset of stage II colon cancer patients with excellent prognosis and who therefore do not require referral for adjuvant chemotherapy; 2. Investigate whether there is a survival benefit from the use of adjuvant chemotherapy in a population-based cohort of stage II colon cancer; 3. Investigate stage III colon cancer patients for evidence of predictive markers for response to 5FU chemotherapy; 4. Investigate CRC for age-related differences in clinico-pathological and molecular features. Hypotheses to be tested: 1. A subset of good prognosis stage II colon cancers can be defined using routine pathological markers; 2. Females colon cancer patients gain more survival advantage from 5FU chemotherapy than males; 3. Tumours from young CRC patients have different molecular characteristics to those from older patients; 4. The underlying molecular characteristics of tumour can impact upon the response to 5FU chemotherapy. Methods: The study cohort consisted of 5,971 cases diagnosed between 1993 and 2003 representing over 90% of the CRCs diagnosed in the state of Western Australia. Results: The major findings of this translational research into colon cancer can be summarized as follows: The morphological features of serosal and vascular invasion allow for prognostic stratification of stage II colon cancer into

This thesis includes the synthesis, characterisation, antioxidant and antimicrobial activities of Cu(II)-, Co(II)- and Co(III) complexes with N,N'-bis(3- methoxysalicylaldimine)propan-2-ol, 2-OH-oVANPN. The Schiff base ligand, 2-OHoVANPN, is derived from o-vanillin and 1,3-diaminopropan-2-ol. The o-vanillin condensed with 1,3-diaminopropan-2-ol in a 2:1 molar ratio yields this potential tetraor pentadentate ligand. The complexes synthesized are tetra (or penta or hexa) coordinated. Formation of the complexes is symbolized as follows:- MX₂ + 2-OH-oVANPN (2:1) -> [M(2-OH-oVANPN)Xn] + HnX MX₂ + 2-OH-oVANPN (2:1) -> [Mn(2-OH-oVANPN)OH] + H₂X₂ MX₂ + (o-vanillin : diaminopropanol) (1:1) -> [M(1:1)X₂] MX₂ + (o-vanillin : diaminopropanol) (1:1) -> [M₃(1:1)X₄] M = Cu(II), Co(II) or Co(III); X = Cl; n = 1, 2. Their structural features have been deduced from their elemental analytical data, IR spectral data, and electronic spectral data. With the exception of {Cu₃(C₁₁H₁₄N₂O₃)(Cl)₄(H₂O)₆}(A4), the Cu(II) complexes were monomeric with 2-OH-oVANPN acting as a tetradentate ligand. A binuclear Co(II) complex, [Co₂(C₁₉H₁₉N₂O₅)(OH)] (B1), was synthesised and the rest of the Co(II) and Co(III) complexes were monomeric with chloride ions coordinating to the metal centre in some cases. Electronic data suggest that the cobalt(II) complexes have octahedral geometries and the copper(II) complexes have square planar structures – Co(III) is likely to be octahedral. Thermal analyses, which included the copper-block-method for determining sublimation temperatures, revealed that some copper(II) and cobalt(II) complexes are hygroscopic and sublime at 200 °C and below. DSC analyses of the Cu(II) complexes gave exotherms around 300 °C for complexes K[Cu(C₁₉H₂₀N₂O₅)(OH)]·2H₂O (A1) and [Cu(C₁₁H15N₂O₃)(Cl)₂]·2H₂O (A2) and above 400 °C for [Cu(C₁₁H₁₆N₂O₃)(Cl)₂] (A3) and {Cu₃(C₁₁H₁₄N₂O₃)(Cl)₄(H₂O)₆} (A4). Antioxidant studies were carried out against the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·). The cobalt(II) complex, [Co₂(C₁₉H₁₉N₂O₅)(OH)] (B1), which was synthesized in the presence of KOH, had no antioxidant activity, whilst the other cobalt(II) complexes, [Co(C₁₇H₁₇N₂O₅(Cl))]·1½H₂O (B2), [Co(C₁₉H₂₂N₂O₅) (Cl)₂]·5½H₂O (B3) and [Co(C₁₉H₂₂N₂O₅)(Cl)₂]·5½H₂O (B4), which were synthesised in the absence of KOH, demonstrated antioxidant activity. The latter complexes are candidates for cancer cell line testing, while [Cu(C₁₁H₁₆N₂O₃)(Cl)₂] (A3), {Cu₃(C₁₁H₁₄N₂O₃)(Cl)₄(H₂O)₆} (A4), [Co(C₁₉H₂₁N₂O₅)(Cl)₂ ]·5H₂O (C2) and [Co(C₁₉H₂₀N₂O₅)(Cl)]·3H₂O (C3) may show anticancer activity through possible hydrolysis products. Most of the complexes synthesized displayed antimicrobial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus niger and Candida albicans. The results indicated that complexes [Cu(C₁₁H₁₆N₂O₃)(Cl)₂](A3), [Co(C₁₉H₂₂N₂O₅)(Cl)₂]·5½H₂O (B3) and [Co(C₁₉H₂₁N₂O₅)(Cl)₂ ]·5H₂O (C2) are active against the Gram-negative Ps. aeruginosa and that the ligand, 2-OH-oVANPN, did not have any activity. The same trend was observed with 2-OH-oVANPN, {Cu₃(C₁₁H₁₄N₂O₃)(Cl)4(H₂O)₆} (A4) and [Co(C₁₉H₂₀N₂O₅)(Cl)]·3H₂O (C3) against the Gram-positive S. aureus. As for activity against E. coli and C. albicans, some complexes showed more activity than the ligand. There is an observed trend here that the metal complexes are more active (toxic) than the corresponding ligand, which is in agreement with Tweedy’s chelation theory.

La plupart des molécules utilisées en chimiothérapie conventionnelle, bien qu’ayant des cibles moléculaires différentes, induisent dans la majorité des cas une mort cellulaire par apoptose. Or, de plus en plus de chimiorésistances se rencontrent au niveau des cellules cancéreuses vis-à-vis de ce type de molécules. Face à cette situation il devient urgent de trouver des molécules ayant des mécanismes d’action différents et capables de court-circuiter spécifiquement les mécanismes de résistance des cellules cancéreuses. <p>La stratégie mise en place lors de ce travail a été de partir d’une molécule naturelle issue d’un extrait de la racine de Glycyrrhiza glabra qui présentait déjà une activité anti tumorale marquée. L’intérêt du travail a été de dériver l’acide 18β-glycyrrhétinique de manière originale afin de potentialiser son effet anticancéreux, notamment vis-à-vis de huit lignées cellulaires présentant des résistances plus ou moins marquées aux stimuli pro-apoptotiques. Ainsi après avoir caractérisé la pureté et la stabilité de cette série de nouvelles molécules, nous avons retenu les dérivés les plus intéressants en termes d’inhibition in vitro de la prolifération cellulaire. Sur base de ce premier choix, nous avons investigué des cibles spécifiques décrites dans la littérature pour les hémidérivés de l’acide 18β-glycyrrhétinique :le protéasome 26S et le récepteur nucléaire PPARγ. Cette étude nous a permis de retenir un dérivé en particulier capable d’inhiber à 50% les trois sites catalytiques du protéasome sans toutefois inhiber PPARγ :le N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b). Nous avons ensuite évalué ce composé sur un ensemble de 333 kinases afin de déterminer un profil antitumoral plus large pour ce type de molécule. <p>Le profil pharmacologique in vitro de ce dérivé de l’acide 18β-glycyrrhétinique nous a amenés à étudier son comportement in vivo chez la souris saine. A cette fin, une étude de préformulation nous a permis de définir une formulation galénique optimale pour ce composé, la nanoémulsion qui a servi à déterminer une dose maximale tolérée (indice DMT) par la souris saine. Nous avons ensuite travaillé à une dose non toxique pour déterminer le profil pharmacocinétique plasmatique chez la souris saine, par voie d’administration intraveineuse et par voie orale. <p>Les conclusions de cette étude nous montrent que le dérivé de l’acide 18β-glycyrrhétinique que nous avons mis au point présente de remarquables caractéristiques pharmacologiques in vitro et un comportement in vivo proche de la molécule naturelle. Des études d’activité in vivo devraient débuter prochainement.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

No description available.

Orientadores: José Andrés Yunes, Nilson Ivo Tonin Zanchin / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-24T06:00:33Z (GMT). No. of bitstreams: 1 Silveira_AndreBortolini_D.pdf: 16883235 bytes, checksum: e0759c48520d471791a5272349e1a837 (MD5) Previous issue date: 2013 / Resumo: A via PI3K está frequentemente hiperativada em células primárias de leucemia linfoide aguda T (LLA-T) pediátrica, característica previamente associada à resistência a glucocorticoides. Pacientes cujas células leucêmicas apresentam mutações em PTEN, o principal regulador negativo de PI3K, podem apresentar maior risco de falha na terapia de indução e recaída. Neste estudo, uma assinatura baseada em expressão gênica foi utilizada para acessar o nível de ativação da via PI3K em amostras diagnósticas de LLA-T. Nós identificamos Myc como um importante integrador da atividade de sinalização por PI3K e observamos que maior atividade da via está associada à resistência a glucocorticoides e pior prognóstico. O inibidor de PI3K AS605240 mostrou atividade antileucêmica e forte sinergismo com glucocorticoides tanto in vitro como em um modelo xenográfico de LLA-T em camundongos NOD/SCID. Em contraste, a inibição de PI3K resultou em antagonismo com metotrexato e daunorrubicina, drogas que atuam preferencialmente em células em divisão. Esta interação antagonística, no entanto, pôde ser revertida pelo uso de um esquema temporal específico de administração das drogas. Nossos dados indicam os potenciais benefícios e limitações para a incorporação de inibidores de PI3K na terapia da LLA-T / Abstract: The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. In this study, a PI3K gene expression signature was used as readout of PI3K activity in diagnostic T-ALL samples. We identified Myc as an important downstream integrator of PI3K pathway activity in T-ALL and found that higher PI3K activity is associated with glucocorticoid resistance and worse clinical outcome. The PI3K inhibitor AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy. OBSERVAÇÃOArquivo pdf com capa, página de rosto, folha de assinatura da banca examinadora, resumo e abstract foi editado segundo informação CCPG/002/2013 / Doutorado / Genetica Animal e Evolução / Doutor em Genetica e Biologia Molecular

Introdução: A cardiotoxicidade aguda e subaguda pode ser caracterizada pelo prolongamento do intervalo QT corrigido (QTc) e demais medidas derivadas do intervalo QTc, como: a dispersão do intervalo QTc (QTdc) e a dispersão transmural da repolarização (DTpTe). No entanto, ainda não foi determinado se pacientes com neoplasia de mama submetidas ao esquema quimioterápico com antraciclina, ciclofosfamida e taxano (ACT) podem apresentar prolongamento do intervalo QTc, da QTdc e da DTpTe. Os objetivos deste estudo foram 1. avaliar o efeito da quimioterapia ACT no intervalo QTc, 2. avaliar o efeito da quimioterapia ACT na QTdc e na DTpTe, 3.avaliar os biomarcadores cardioespecíficos como a troponina e o peptídeo natriurético do tipo B (BNP), e 4. avaliar manifestações clínicas de cardiotoxicidade, como a presença de: arritmias cardíacas, insuficiência cardíaca (ICC), angina e morte cardiovascular em pacientes com neoplasia de mama. Métodos: Trata-se de um estudo de coorte prospectivo em que 23 pacientes com neoplasia de mama não metastática foram acompanhadas durante o tratamento quimioterápico com o esquema ACT. As medidas do intervalo QTc, da QTdc e da DTpTe foram determinadas pelo eletrocardiograma (ECG) de 12 derivações antes do início da quimioterapia (basal), após a primeira fase com antraciclina e ciclofosfamida (AC), e ao final do tratamento com taxano (T). Biomarcadores como troponina e BNP também foram analisados. Resultados: Quando comparado aos valores basais, houve prolongamento do intervalo QTc após a primeira fase da quimioterapia - AC, 439,7 ms ± 33,2 vs 472,5 ms ± 36,3, (p = 0,001) e ao final do tratamento com taxano, 439,7 ms ± 33,2 vs 467,9 ms ± 42,6, (p < 0,001). A dosagem média de troponina sérica, quando comparada aos valores basais, apresentou elevação após o término da primeira fase da quimioterapia - AC, 6,0 pg/mL [min-max. 6,0 - 22,0] vs 23,0 pg/mL [min-max. 6,0 - 85,0], (p < 0,001) e ao final do tratamento com taxano, 6,0 pg/mL [min-max. 6,0 - 22,0] vs 25,0 pg/mL [min-max. 6,0 - 80,0], (p < 0,001). A QTdc, a DTpTe e os níveis séricos de BNP não mostraram diferenças com significância estatística. Durante o seguimento clínico não houve nenhum óbito e nenhuma constatação de angina, ICC e arritmias cardíacas. Conclusão: Em pacientes com neoplasia de mama não metastática submetidas à quimioterapia com esquema ACT, houve prolongamento do intervalo QTc e elevação dos níveis séricos de troponina / Background: Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as the QTc dispersion (QTdc) and the transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unknown whether breast cancer patients who undergo a chemotherapy regimen with anthracycline (A; doxorubicin), cyclophosphamide (C) and taxane (T; ACT regimen) may present with QTc, QTdc and DTpTe prolongation. Methods: Twenty-three patients with breast cancer were followed up in a prospective study during ACT chemotherapy. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), after the first phase of anthracycline and cyclophosphamide (AC), and after T treatment. Biomarkers such as troponin and B-type natriuretic peptide (BNP) were also measured. Results: When compared to baseline values, the QTc interval showed a statistically significant prolongation after the AC phase (439.7 ± 33.2 msec vs 472.5 ± 36.3 msec, p = 0.001) and after T treatment (439.7 ± 33.2 msec vs 467.9 ± 42.6 msec, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0 - 85.0] vs 6.0 pg/mL [min-max: 6.0 - 22.0], p < 0.001) and again after T treatment (25.0 pg/mL [min-max: 6.0 - 80.0] vs 6.0 pg/mL [min-max: 6.0 - 22.0], p < 0.001) compared to the baseline values. Conclusion: In patients with non-metastatic breast cancer who underwent ACT chemotherapy, a statistically significant QTc prolongation and an elevation in serum troponin levels were observed

Background: Human head and neck squamous cell carcinoma (HNSCC) fundamentally vary in their susceptibility to different cytotoxic drugs and treatment modalities. There is at present no clinically accepted test system to predict the most effective therapy for an individual patient. Methods: Therefore, we established tumor-derived slice cultures which can be kept in vitro for at least six days. Upon treatment with cisplatin, docetaxel and cetuximab, slices were fixed and paraffin sections were cut for histopathological analysis. Results: Apoptotic fragmentation, activation of caspase 3, and cell loss were observed in treated tumor slices. Counts of nuclei per field in untreated compared to treated slices deriving from the same tumor allowed estimation of the anti-neoplastic activity of individual drugs on an individual tumor. Conclusion: HNSCC-derived slice cultures survive well in vitro and may serve to improve personalized therapies, but also to detect mechanisms of tumor resistance by harvesting surviving tumor cells after treatment.