Yes / Background: Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases. Methods: We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway. Results: Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance. Conclusions: Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer.

Yes / Purpose: Despite positive responses in phase II clinical trials, the bioreductive prodrug apaziquone failed to achieve statistically significant activity in non-muscle invasive bladder cancer in phase III trials. Apaziquone was administered shortly after transurethral resection and here we test the hypothesis that haematuria inactivates apaziquone. Methods: HPLC analysis was used to determine the ability of human whole blood to metabolise apaziquone ex vivo. An in vitro model of haematuria was developed and the response of RT112 and EJ138 cells following a 1-h exposure to apaziquone was determined in the presence of urine plus or minus whole blood or lysed whole blood. Results: HPLC analysis demonstrated that apaziquone is metabolised by human whole blood with a half-life of 78.6±23.0 min. As a model for haematuria, incubation of cells in media containing up to 75% buffered (pH 7.4) urine and 25% whole blood was not toxic to cells for a 1-h exposure period. Whole blood (5% v/v) significantly (p<0.01) reduced the potency of apaziquone in this experimental model. Lysed whole blood also significantly (p<0.05) reduced cell growth, although higher concentrations were required to achieve an effect (15% v/v). Conclusions: The results of this study demonstrate that haematuria can reduce the potency of apaziquone in this experimental model. These findings impact upon the design of further phase III clinical trials and strongly suggest that apaziquone should not be administered immediately after transurethral resection of non-muscle invasive bladder cancer when haematuria is common. / Financial support from Spectrum Pharmaceuticals Inc. for the conduct of the experiments.

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

Muscle invasive bladder cancer (MIBC) has a poor prognosis. Currently, therapy consists of radical radiotherapy or cystectomy with or without chemotherapy. The average age of patients with MIBC is high and older patients are less able to tolerate surgery or chemoradiation due to their impaired physical fitness and generally poor renal function. There is an urgent need to find new treatment regimes that are both tolerable and effective. The aims of this project were to investigate the radiosensitising effects of the histone deacetylase (HDAC) inhibitor panobinostat in bladder cancer cell lines, with the ultimate goal of proposing a novel radiosensitising therapy for MIBC, and to study the effects of panobinostat on the major DNA double strand break (DSB) repair pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), to determine the predominant pathway targeted and to look further upstream at effects on the MRE11/RAD50/NBS1 (MRN) complex. The HDAC inhibitor panobinostat was found to be toxic in the low nanomolar range and significant radiosensitising effects were demonstrated at doses lower than IC50 in all the bladder cell lines studied. The radiosensitising effect of panobinostat was not influenced by TP53 status, which is generally regarded as an important determinant of bladder cancer response to radiotherapy. In the “synthetic lethality” bladder cancer cell model, panobinostat predominantly targets the HR pathway, reportedly the only proficient DNA repair pathway in MIBC. HR proteins RAD51 and CtIP were downregulated upon panobinostat treatment in a dose-dependent manner. Upstream, MRE11 and NBS1 proteins were also targeted by panobinostat, with levels slightly decreased in RT112 and T24 cells and in CAL29 cells post-ionising radiation. In summary, the HDAC inhibitor panobinostat was shown to be an efficient radiosensitiser in bladder cancer cells at low toxic doses and to predominantly target the HR pathway. These findings are promising and may contribute towards establishing a novel combination therapy of panobinostat with IR for MIBC patients.

O câncer de bexiga é uma neoplasia urogenital que acomete homens e mulheres, sendo que somente no Brasil 8.600 novos casos ao ano são diagnosticados. Cistoscopia transuretral é a conduta padrão no diagnóstico e acompanhamento do câncer de bexiga. Entretanto, tal procedimento é extremamente invasivo e doloroso além de ter elevado custo e não garantir todos os resultados. Assim, busca-se por marcadores moleculares que possam auxiliar no diagnóstico e progressão do câncer de bexiga, bem como diminuir a necessidade de exames invasivos no acompanhamento de pacientes tratados. Nesse sentido, a urina tem papel de destaque como fonte de biomarcadores devido principalmente ao seu caráter não invasivo. <br /> Nesse trabalho foram utilizadas duas abordagens \'ômicas\': proteômica e metabolômica, para a busca de biomarcadores em urina para o diagnóstico e prognóstico do câncer de bexiga, respectivamente. Com a abordagem proteômica buscou-se apenas por biomarcadores para o diagnóstico da doença e, utilizando as técnicas de eletroforese 2-DE, OFFGEL e MS, juntamente com análise estatística multivariada, foi possível identificar 32 proteínas que apresentam-se como potenciais marcadores para o câncer de bexiga. A abordagem metabolômica foi empregada para a busca de biomarcadores para reincidência e progressão da doença. As técnicas analíticas utilizadas nessa abordagem, LC-MS e CE-MS, mostraram-se complementares e, dos resultados obtidos com ambas e avaliados com análise estatística multivariada foi possível indicar 19 metabólitos para reincidência e 23 metabólitos para progressão do câncer de bexiga. <br /> Assim, neste trabalho explorou-se como as ciências \'ômicas\', a qual abrange técnicas analíticas de high-throughput, estatística multivariada e ferramentas de bioinformática auxiliando na descoberta de potenciais biomarcadores não invasivos para o diagnóstico e prognóstico do câncer de bexiga. Portanto, o presente estudo foi de grande importância e relevância à medida que ilustrou como tais técnicas podem potencialmente auxiliar no diagnóstico e prognóstico de doenças e contribuir para tratamentos personalizados no futuro, indicando a potencialidade de estudos dessa natureza. / Bladder cancer is an urogenital cancer affecting men and women, and just in Brazil 8,600 new cases are diagnosed annually. Transurethral cystoscopy is a standard conduct in the diagnosis and monitoring of bladder cancer. However, this procedure is extremely invasive, painful, expensive and does not guarantee the best results. Thus, the searching for molecular markers may assist in the diagnosis and monitoring of bladder cancer, as well as decreasing the need for invasive tests in the monitoring of patients treatment. In this way, urine shows an important role as a source of biomarkers, mainly due to its non-invasive nature. <br /> In this work we used two \'omics\' approaches: proteomics and metabolomics, to search for biomarkers in urine for the diagnosis and progression of bladder cancer, respectively. The proteomics approach was explored for biomarkers for diagnosing disease. Using 2-DE, OFFGEL electrophoresis, and MS techniques, as well multivariate statistical analysis, they were identified 32 proteins that may be pointed as potential markers for bladder cancer. The metabolomics approach was used to search for biomarkers for progression and recurrence of the disease. The analytical techniques used for this approach, LC-MS and CE-MS, were complementary to each other and the results evaluated with multivariate statistical analysis indicated that 19 metabolites for recurrence and 23 metabolites for progression of bladder cancer could possibly be used for validation studies. <br /> Thus, we demonstrated how the \'omics\' sciences, which include high- throughput analytical techniques, multivariate statistical analysis, and bioinformatics tools, aid in the discovery of potential biomarkers for noninvasive diagnosis, evaluate recurrence and monitor progression of bladder cancer. Therefore, this study was of high relevance to demonstrate the potential of such techniques to contribute to studies of personalized medicine.

Les tumeurs de vessie suivent deux voies de progression tumorale. La voie des tumeurs papillaires qui progressent rarement vers des tumeurs invasives mais qui récidivent très fréquemment et la voie des carcinomes in situ (CIS) qui progressent pour envahir le chorion puis le muscle. Les tumeurs infiltrant le muscle sont de mauvais pronostic et les traitements par chimiothérapie restent d’efficacité limitée. Il est alors important d’en comprendre les bases moléculaires. Les microRNAs sont d’importants régulateurs de l’expression post-transcriptionnelle des gènes. Des perturbations de leur expression et/ou de leur activité contribuent au développement tumoral en dérégulant l’expression de gènes clés dans les cancers. Nos travaux ont porté sur l’étude de l’expression et des fonctions des microRNAs dans la carcinogenèse urothéliale. Dans la première partie, nous avons choisi d’étudier, par une approche de gènes candidats, miR-155, un oncomiR dont l’expression dérégulée a été rapportée dans plusieurs cancers mais pas encore dans le cancer de la vessie. J’ai identifié une surexpression significative de ce miARN dans un sous-groupe de cancers invasifs de vessie. Ensuite, j’ai montré par des analyses fonctionnelles, le rôle de miR-155 dans l’invasion et la migration tumorale mais pas dans la prolifération cellulaire. Dans la deuxième partie, nous avons utilisé une approche plus globale. J’ai d'abord effectué une revue extensive de la littérature pour rechercher les miR dont l'expression avait été montrée comme dérégulée dans les cancers de vessie et/ou les miR impliqués fonctionnellement dans ce cancer. J’ai ensuite réalisé une analyse multiparamétrique en intégrant les données d'expression de ces miR, les données anatomopathologiques et moléculaires (stade et grade, statut mutationel de TP53 et FGFR3, phénotype épigénétique MRES et signature CIS) et les données du transcriptome (puces Affymetrix U133 Plus 2.0), des altérations génomiques (puces Illumina 370.000 sondes) et de méthylation (puces Illumina 27.000 sondes). Ce travail m’a permis, d'identifier des miR associés à l'une des deux voies de progression identifiées dans les cancers de vessie et de proposer des cibles candidates de ces miR. La recherche des altérations épigénétiques pouvant affecter l’expression de ces miR a permis d’identifier une association significative entre l’expression d’un miARN (miR-17-5p) et la méthylation d’un promoteur. En revanche les altérations génétiques n’ont été associées à aucune expression de miR. Ce travail propose une liste de très bons candidats miARNs pour lesquels des études fonctionnelles pourront être envisagées au-delà de mon travail de thèse. / Bladder tumors are characterized by two progression pathways. The first pathway leads to the developpement of papillary tumors, which are at high risk of recurrence but that rarely progress to invasive tumors. Another pathway involves carcinoma in situ (CIS), which often progresses by first invading the lamina propria and then the muscle. Tumors infiltrating the muscle have a poor prognosis and chemotherapy regimens are of limited benefits. It is yet important to understand the molecular basis underlying these events. The microRNAs are important regulators of post-transcriptional gene expression. Alteration in their expression and /or activity is believed to contribute to tumor development by deregulating the expression of cancer-related genes. Our work has been focused on studying the expression and function of microRNAs in urothelial carcinogenesis. In the first part, we employed a candidate gene approach to study miR-155, a oncomiR whose dysregulated expression has been reported in many cancers, but not in bladder cancer. I identified a significant overexpression of this miRNA in a subgroup of invasive bladder cancers. Next, I demonstrated a role for miR-155 in tumor invasion and migration, without any apparent effect on cell proliferation. In the second part, we used a more comprehensive approach in which I first conducted an extensive review of the literature to search for miR whose expression was already found to be deregulated and/or miR functionally involved in bladder cancer. I then performed a multiparametric analysis by integrating expression data of miR, pathological and molecular data (stage and grade, mutational status of FGFR3 and TP53, MRES epigenetic phenotype and CIS signature) data of the transcriptome (Affymetrix U133 Plus 2.0), genomic alterations (370,000 chips Illumina probes) and methylation (Illumina chips 27,000 probes). This work allowed us to identify miRs associated with one or the other pathway linked to progression of bladder cancer and also, it revealed candidate targets for these miRs. The search for epigenetic alterations capable to affect the expression of those miRs showed significant association between expression of a particular miRNA (miR-17-5p) and the methylation of its promoter. Genetic alterations however, have failed to associate with expression of miR. Finally, this work suggests a list of good candidates miRNAs for which future functional studies should help to get insight into the role of these miRNAs

O câncer de bexiga é uma neoplasia urogenital que acomete homens e mulheres, sendo que somente no Brasil 8.600 novos casos ao ano são diagnosticados. Cistoscopia transuretral é a conduta padrão no diagnóstico e acompanhamento do câncer de bexiga. Entretanto, tal procedimento é extremamente invasivo e doloroso além de ter elevado custo e não garantir todos os resultados. Assim, busca-se por marcadores moleculares que possam auxiliar no diagnóstico e progressão do câncer de bexiga, bem como diminuir a necessidade de exames invasivos no acompanhamento de pacientes tratados. Nesse sentido, a urina tem papel de destaque como fonte de biomarcadores devido principalmente ao seu caráter não invasivo. <br /> Nesse trabalho foram utilizadas duas abordagens \'ômicas\': proteômica e metabolômica, para a busca de biomarcadores em urina para o diagnóstico e prognóstico do câncer de bexiga, respectivamente. Com a abordagem proteômica buscou-se apenas por biomarcadores para o diagnóstico da doença e, utilizando as técnicas de eletroforese 2-DE, OFFGEL e MS, juntamente com análise estatística multivariada, foi possível identificar 32 proteínas que apresentam-se como potenciais marcadores para o câncer de bexiga. A abordagem metabolômica foi empregada para a busca de biomarcadores para reincidência e progressão da doença. As técnicas analíticas utilizadas nessa abordagem, LC-MS e CE-MS, mostraram-se complementares e, dos resultados obtidos com ambas e avaliados com análise estatística multivariada foi possível indicar 19 metabólitos para reincidência e 23 metabólitos para progressão do câncer de bexiga. <br /> Assim, neste trabalho explorou-se como as ciências \'ômicas\', a qual abrange técnicas analíticas de high-throughput, estatística multivariada e ferramentas de bioinformática auxiliando na descoberta de potenciais biomarcadores não invasivos para o diagnóstico e prognóstico do câncer de bexiga. Portanto, o presente estudo foi de grande importância e relevância à medida que ilustrou como tais técnicas podem potencialmente auxiliar no diagnóstico e prognóstico de doenças e contribuir para tratamentos personalizados no futuro, indicando a potencialidade de estudos dessa natureza. / Bladder cancer is an urogenital cancer affecting men and women, and just in Brazil 8,600 new cases are diagnosed annually. Transurethral cystoscopy is a standard conduct in the diagnosis and monitoring of bladder cancer. However, this procedure is extremely invasive, painful, expensive and does not guarantee the best results. Thus, the searching for molecular markers may assist in the diagnosis and monitoring of bladder cancer, as well as decreasing the need for invasive tests in the monitoring of patients treatment. In this way, urine shows an important role as a source of biomarkers, mainly due to its non-invasive nature. <br /> In this work we used two \'omics\' approaches: proteomics and metabolomics, to search for biomarkers in urine for the diagnosis and progression of bladder cancer, respectively. The proteomics approach was explored for biomarkers for diagnosing disease. Using 2-DE, OFFGEL electrophoresis, and MS techniques, as well multivariate statistical analysis, they were identified 32 proteins that may be pointed as potential markers for bladder cancer. The metabolomics approach was used to search for biomarkers for progression and recurrence of the disease. The analytical techniques used for this approach, LC-MS and CE-MS, were complementary to each other and the results evaluated with multivariate statistical analysis indicated that 19 metabolites for recurrence and 23 metabolites for progression of bladder cancer could possibly be used for validation studies. <br /> Thus, we demonstrated how the \'omics\' sciences, which include high- throughput analytical techniques, multivariate statistical analysis, and bioinformatics tools, aid in the discovery of potential biomarkers for noninvasive diagnosis, evaluate recurrence and monitor progression of bladder cancer. Therefore, this study was of high relevance to demonstrate the potential of such techniques to contribute to studies of personalized medicine.

Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. We demonstrated that curcumin inhibited 253JB-V and KU7 bladder cancer cell growth, and this was accompanied by induction of apoptosis and decreased expression of the proapoptotic protein survivin and the angiogenic proteins vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Since expression of survivin, VEGF and VEGFR1 are dependent on specificity protein (Sp) transcription factors, we also investigated the effects of curcumin on downregulation of Sp protein expression as an underlying mechanism for the apoptotic and antiangiogenic activity of this compound. Curcumin decreases expression of Sp1, Sp3 and Sp4 in blader cancer cells indicating that the cancer chemotherapeutic activity of curcumin is due, in part, to decreased expression of Sp transcription factors and Sp-dependent genes. Betulinic acid (BA) and curcumin are phytochemical anticancer agents, and we hypothesized that both compounds decrease EGFR expression in bladder cancer through downregulation of specificity protein (Sp) transcription factors. BA and curcumin decreased expression of EGFR, Sp1, Sp3, Sp4 and Sp-dependent proteins in 253JB-V and KU7 cells; EGFR was also decreased in cells transfected with a cocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3 and Sp4 showing that EGFR is an Sp-regulated gene. Methyl 2-cyano-3,11-dioxo-18?-olean-1,12- dien-30-oate (CDODA-Me) is a synthetic triterpenoid derived from glycyrrhetinic acid which inhibits proliferation of KU7 and 253JB-V bladder cancer cells. CDODA-Me also decreased expression of specificity protein-1 (Sp1), Sp3 and Sp4 transcription factors. Similar results were observed for a structurally-related triterpenoid, methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me), which is currently in clinical trials for treatment of leukemia. Celastrol, a naturally occurring triterpenoid acid from an ivy-like vine exhibits anticancer activity against bladder cancer cells. Celastrol decreased cell proliferation, induced apoptosis and decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and several Sp-dependent genes like Fibroblast growth factor receptor 3 (FGFR3). In vivo studies using KU7 cells as xenografts showed that celastrol represents novel class of anticancer drugs that acts, in part, through targeting downregulation of Sp transcription factors.

Objective: This study attempts to estimate the proportion of incident cases of bladder cancer in Ontario, Canada that is due to exposure to occupational carcinogens. Methods: The population attributable risk approach is used to estimate the proportion of bladder cancer in Ontario that is due to occupation. Risk ratios were obtained from a review of epidemiologic literature using a priori inclusion and exclusion criteria. Summary risk estimates for each bladder carcinogen included were calculated using RevMan 4.2. The CAREX Canada database provided Ontario-specific estimates of the proportion of workers exposed to bladder carcinogens. Results: In Ontario, the proportion of bladder cancer due to occupational exposure is approximately 5.6% (95% CI 0.2% to 14%). Based on the incident number of bladder cancer cases in 2001 in Ontario, it is estimated that approximately 52 new cases of bladder cancer were due to occupational exposure to polycyclic aromatic hydrocarbons (PAHs), diesel exhaust, aromatic amines and 2-naphthylamine. An alternate interpretation is if these occupational exposures were eliminated, 52 cases of bladder cancer per year in Ontario alone could be avoided. Conclusion and Recommendations: The current study advances our knowledge of the extent to which specific occupational bladder carcinogens contribute to the overall bladder cancer burden in Ontario. The current study highlights the utility of the CAREX Canada database in advancing current knowledge on the burden of occupational cancer in Ontario. The methods used to estimate the proportion of bladder cancer attributable to occupational exposure in Ontario may be replicated to estimate the proportion of cancer in Ontario that is due to occupational exposure. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2008-08-29 20:08:46.713

<p>Mild hyperthermia (39°C-43°C) has numerous therapeutic benefits as an adjuvant therapy in the treatment of a variety of tumor types. Hyperthermia increases tumor blood flow and vascular permeability, promoting drug delivery and tumor oxygenation. Hyperthermia enhances the uptake and efficacy of numerous chemotherapeutic agents, including cisplatin, resulting in increased cytotoxicity. In addition to these biological responses, hyperthermia can be used as a drug-release trigger for temperature-sensitive nanoparticles, resulting in an improved and more targeted drug delivery system. Cisplatin was chosen because 1) it shows broad spectrum activity against a wide range of heatable cancers (i.e., those in sites such as the pancreas, colon and rectum, cervix and bladder, and 2) the same hyperthermic temperatures that enable temperature-sensitive lipsome-drug release also enhance cisplatin-induced cytotoxicity.</p><p>The role of hyperthermia in enhancing cisplatin delivery and cytotoxicity was investigated at both the cellular and tissue levels. While hyperthermia treatment is applicable to a variety of tumor types, the focus of this work was on bladder cancer. The synergistic effects of hyperthermia and cisplatin were investigated, along with the role of copper transport protein 1 (Ctr1) in this process. In addition, cisplatin was encapsulated within temperature-sensitive liposomes, which were used in combination with hyperthermia for targeted drug delivery. These studies demonstrated that the combination of cisplatin and hyperthermia improved drug delivery, and potentially anti-tumor efficacy, and that targeted delivery was enhanced through incorporation of temperature-sensitive liposomes. As many current methods for administering bladder hyperthermia have drawbacks, such as invasiveness and regional heating, the final aim of this study was to develop and test a less-invasive and more focused preclinical bladder heating device in a rat model. </p><p>Hyperthermia sensitizes cells to the cytotoxic effects of the commonly used chemotherapeutic agent cisplatin by increasing drug accumulation and subsequent platinum-DNA adduct formation. However, the molecular mechanisms underlying this enhancement remain unclear. Understanding the fundamental mechanisms involved in the synergistic interaction is necessary to increase the therapeutic benefits of this combination in the clinic. The synergism between the anti-cancer benefits of cisplatin and the drug delivery benefits of hyperthermia may offer a novel and more effective treatment for many cancer patients. We hypothesized that hyperthermia increases cisplatin accumulation and efficacy in part by modulating the function of Ctr1, a major regulator of cellular cisplatin uptake. To test this hypothesis, we examined the significance of Ctr1 during combined hyperthermia and cisplatin therapies and assessed the importance of cisplatin- and hyperthermia-induced Ctr1 multimerization in enhancing cisplatin cytotoxicity. We observed increased Ctr1 multimerization following hyperthermia treatment (41°C) in vitro, compared to normothermic controls (37°C), suggesting that this may be a mechanism for increased cisplatin uptake in heat-treated cells. The impact of increased Ctr1 multimerization was evaluated by measuring platinum accumulation in wild-type (WT) and Ctr1-/- cells. WT cells contained greater levels of platinum compared to Ctr1-/- cells. A further increase in platinum was observed following hyperthermia treatment, but only in the WT cells. Hyperthermia enhanced cisplatin-mediated cytotoxicity in WT cells with a dose-modifying factor (DMF) of 1.8 compared to 1.4 in Ctr1-/- cells. Our data suggest that heat increases Ctr1 activity by increasing multimerization, resulting in enhanced drug accumulation. Although we recognize that the effect of heat on cells is multi-factorial, our results support the hypothesis that Ctr1 is, in part, involved in the synergistic interaction observed with cisplatin and hyperthermia treatment. </p><p>In addition to assessing cisplatin delivery at the cellular level, we evaluated cisplatin delivery at the tissue level, using novel cisplatin-loaded temperature-sensitive liposomes. We hypothesized that delivering cisplatin encapsulated in liposomes under hyperthermic conditions would improve the pharmacokinetic profiles of cisplatin, increase drug delivery to the tumor, decrease normal tissue toxicity, and enhance the anti-tumor activity of cisplatin. We successfully prepared temperature-sensitive liposomes loaded with cisplatin and demonstrated that heat (42°C) sensitizes cisplatin-resistant cells to the cytotoxic effects of cisplatin in vitro. </p><p>Decreased toxicity was observed in animals treated with the cisplatin liposome (± heat) compared to the free drug treatments. A pharmacokinetic study of cisplatin-loaded temperature-sensitive liposomes and free drug was performed in tumor-bearing mice under normothermic and hyperthermic conditions. Cisplatin half-life in plasma was increased following liposome treatment compared to free cisplatin, and cisplatin delivery to the tumors was greatest in mice that received liposomal cisplatin under hyperthermia. These initial in vivo data demonstrate the potential effectiveness of this cisplatin-loaded liposome formulation in the treatment of certain types of cancer. To assess the anti-cancer efficacy of the liposome treatment, a tumor growth delay study was conducted and demonstrated equivalent efficacy for the cisplatin-loaded temperature-sensitive liposome compared to free drug. </p><p>In addition to the liposome work, we developed and evaluated a novel heating device for the bladder. Despite the evidence that hyperthermia is an effective adjuvant treatment strategy, current clinical heating devices are inadequate, warranting the development of a new and improved system. We induced hyperthermia using ferromagnetic nanoparticles and an alternating magnetic field device developed by Actium Biosystems. Initial preclinical studies in a rat model demonstrated preferential bladder heating. However, our preliminary studies show severe toxicity with the direct instillation of the nanoparticles in the bladder, and further studies are needed to potentially modify the nanoparticle coating, the catheterization procedure, as well as to develop a different animal model.</p> / Dissertation