Some compounds, analogous to those found in naturally occurring systems, are found to possess chemotherapeutic activity. Some, in the form of their nucleoside or nucleotide derivatives, are valuable antimetabolites in that they may block normal RNA or DNA polymerisation, or may be incorporated into nucleic acids to form fraudulent, but not necessarily defective, polymers. Modification of natural ring systems, with a view to promoting chemotherapeutic activity is therefore of considerable interest; variation in the position and nature of the modification or ring substituent having a marked effect on chemotherapeutic activity. It is the purpose of this thesis to suggest methods for the facile synthesis of various uracils, pyrazoles and pyrazolo [3,4-d] - pyrimidines with alkyl, aryl and glycosyl substituents such that the nature of the ring substituents is easily varied. To this end a number of ethoxymethylene reagents were prepared which, by reaction with primary amines and hydrazines, would give acyclic intermediates capable of easy cyclisation into the uracil, pyrazole and pyrazolo [3,4-d] pyrimidine ring systems. Variation in the nature of specific substituents being determined by the choice of amine or hydrazine, other substituents being varied by modification of the original reagent. / S.R.G.

Hydrogen sulfide (H2S) is an endogenously produced signaling gas involved in numerous cellular functions. At the appropriate concentration, exogenous administration of this gasotransmitter regulates vasodilation, promotes angiogenesis of endothelial cells, and generally exhibits beneficial effects as an anti-inflammatory and antioperoxidative agent. H2S is also capable of acting as a gaseous chemotherapeutic agent. Therefore, the therapeutic potential of exogenous delivery of H2S is vast. The delivery of H2S is complicated by its gaseous nature. Under physiologically relevant conditions, H2S is rapidly depleted from solution by oxidation and/or degassing. Therefore, direct exogenous delivery is difficult. To date, most studies have employed Na2S as a convenient H2S source. However, the rapid surge in H2S concentration upon Na2S dissolution followed by its rapid decline poorly mimics the sustained production of low concentrations of H2S that occurs in biological systems. We synthesized a library of S-aroylthiooximes (SATOs)—H2S-releasing compounds that more aptly mimic in vivo H2S concentrations. SATOs are synthesized via reaction of a S-aroylthiohydroxylamine and an aldehyde or ketone. SATOs release H2S in response to a thiol functionality. H2S release from SATOs could be controlled, with H2S release half-lives on the order of minutes to hours. SATO chemistry was utilized to prepare H2S-releasing polymers. Copolymers prepared using RAFT polymerization could be functionalized with SATOs with conversions > 99%, and these polymers released H2S on a similar timescale to our small molecule donors, confirming the viability of SATO formation as a post-polymerization modification strategy. SATO-functionalized polymer amphiphiles were prepared that self-assembled into micelles or vesicles based on their composition. H2S was released from these polymer assemblies more slowly than from the small molecules and statistical polymers. These H2S-releasing micelles were employed in in vitro cytotoxicity studies. H2S released from the micelles was found to be selectively toxic to human colon cancer cells compared with healthy fibroblasts. These polymeric micelle donors outperformed existing H2S donors in terms of their toxicity towards cancer cells. The observed enhanced toxicity was suspected to arise from the slow and sustained release of H2S from the micelles. / Ph. D.

Os tumores de cabeça e pescoço ocupam o sexto lugar no ranking de incidência mundial, e estão localizados na região da face, fossas nasais, seios paranasais, boca, faringe, laringe entre outros tecidos moles do pescoço. O tabagismo, o etilismo, a radiação solar e o vírus HPV, são fatores de risco associados a esse tipo de tumors. A terapia combinada de drogas antineoplásicas tem sido utilizada para amenizar os efeitos colaterais e potencializar o tratamento antitumoral. A combinação de paclitaxel e cisplatina tem se mostrado eficaz em tumores sólidos, como o HNSCC. A morte celular induzida pelo paclitaxel é mediada pela ruptura da dinâmica dos microtúbulos normais, já a cisplatina induz ligações cruzadas de DNA estes tratamentos induzem a célula à morte por apoptose. A apoptose é um processo de morte dividido, didaticamente, em via intrínseca (via mitocondrial) e via extrínseca (via receptor de morte). Entender por qual via essas células tumorais são induzidas a morte é fundamental para tentar evitar a resistência dessas células ao tratamento. Nosso objetivo é entender se células tumorais de HNSCC são resistentes ou sensíveis ao tratamento com paclitaxel e cisplatina sozinhos ou em associação. Para isso, realizamos o tratamento da linhagem celular FaDu por um período de 48 horas com as drogas e verificamos sua resistência a indução de morte por esses tratamentos. Os resultados mostraram que o tratamento com paclitaxel não potencializa a morte desta célula, sendo a linhagem FaDu mais sensível ao tratamento com cisplatina e a associação apresenta o mesmo perfil de quando tratada com cisplatina. A morte desta linhagem é dependente de caspases e possui uma preferência pela via extrínseca da apoptose que, consequentemente, induz a morte também pela via intrínseca. A modulação desta morte se dá pelo balanço das proteínas pró- e anti-apoptóticas da família BCL-2 que são responsáveis pela regulação da apoptose, o tratamento com cisplatina induz a expressão da proteína pró-apoptótica BAK e a diminuição das proteínas anti-apoptóticas BCL-2 e BCL-XL. Com os resultados obtidos, concluímos que a associação de paclitaxel e cisplatina não potencializa a morte da linhagem celular FaDu. Contudo, a cisplatina apresentou-se efetiva na indução de morte por apoptose através do aumento da expressão da proteína BAK e a diminuição da expressão das proteínas BCL-2 e BCL-XL. / Head and neck squamous cell carcinoma is the sixth most common cancer in the world, and are located in the region of the face, nasal fossas, sinuses, mouth, pharynx, larynx and other soft tissues of the neck. Tobacco smoke, etilism, solar radiation and HPV are risk factors associated with this type of tumors. Combination therapy of anticancer drugs has been used to alleviate the side effects and potentiate the antitumor treatment. The combination of paclitaxel and cisplatin has been shown to be effective in solid tumors such as HNSCC. The paclitaxel-induced cell death is mediated by disruption of the normal microtubule dynamics, and the cisplatin induced DNA cross-links, these treatments induce cell death by apoptosis. Apoptosis is a death process divided in, intrinsic pathway (mitochondrial pathway) and extrinsic pathway (death receptor pathway). Understand by what pathway those tumor cells which are induced death is important to try and avoid the resistance of these cells to treatment. Our aims understand if HNSCC tumor cells are resistant or sensitive to treatment with paclitaxel and cisplatin alone or in combination. We carried out the treatment of cell line FADU a period of 48 hours with the drug and we verify their resistance to death induction by these treatments. The results showed that treatment with paclitaxel did not potentiate the cell death, in the other hand, FADU cell line appeared to be more sensitive to cisplatin treatment, and the association has the same profile when treated with cisplatin. The death of this line is dependent on caspases and has a preference for the extrinsic pathway of apoptosis, consequently, also induces the death by the intrinsic pathway. The modulation of death is caused by the balance of pro-and anti-apoptotic proteins of BCL-2 family proteins that are responsible for regulation of apoptosis, treatment with cisplatin induces the expression of pro-apoptotic protein BAK and the decrease of anti-apoptotic proteins BCL -2 and BCL-XL. With these results, we conclude that the combination of paclitaxel and cisplatin did not potentiate the cell death of the cell line Fadu. However, cisplatin showed to be effective in induction of death by apoptosis through increased expression of BAK protein and decreased expression of BCL-2 and BCL-XL.

O câncer é umas das principais causas de morte no mundo. Com a falta de critério individual para o tratamento de câncer metastático, a quimioterapia ainda é realizada com fármacos de toxicidade significativa como antraciclinas e taxanos. Portanto, a busca por novos fármacos é de suma importância. Os alquilfosfolipídios constituem uma nova classe de fármacos antineoplásicos, tendo como protótipo a miltefosina, empregada para o tratamento tópico de metástases cutâneas de câncer de mama. No entanto, este fármaco apresenta toxicidade gastrointestinal e ação hemolítica. Neste trabalho, investigou-se a rota sintética da miltefosina, bem como a síntese de novos análogos cicloalquílicos possivelmente menos hemolíticos e menos tóxicos. Para a síntese da miltefosina, 4 etapas foram realizadas: a) obtenção do Dicloreto de fosforoexadecila; b) obtenção de 2-(hexadeciloxi)-3-metil-oxa-1,3,2- oxazofosfolano; c) obtenção do fosfato de 2-(metilamino) etil hexadecila; d) obtenção da miltefosina (hexadecilfosfocolina); sendo o fármaco obtido com sucesso. Em seguida, metodologias de monossubstituição em dióis simétricos foram investigadas para obtenção de ω-hidroxidecil-cicloalquilmetil éteres a serem empregados na rota da miltefosina visando análogos alcoxicicloalquilicos. Diversas tentativas foram empregadas sem sucesso, impedindo-nos de dar continuidade à síntese destes análogos. Partindo-se do reagente cicloexanoetanol e empregando-se a rota de síntese aprimorada da miltefosina, obtivemos o intermediário fosfato de 2-(metilamino)etil cicloexila puro. A última etapa, referente à metilação da amina, resultou em composto dimetilado ao invés do trimetilado esperado. Um ajuste dos parâmetros reacionais como, por exemplo, aumento da concentração dos reagentes de partida, deve resultar no composto planejado. Tanto o intermediário obtido quanto o análogo desejado poderão ser futuramente ensaiados quanto à atividade antitumoral e potencial hemolítico. / Cancer is one of the major causes of death worldwide. Due to the lack of individual standard treatment for metastatic cancer, chemotherapy is still based in the use of significantly toxic drugs like anthracyclines and taxanes. Hence, there is a need to search for new anticancer agents. Alkylphospholipids recently emerged as a new antitumor class and its lead compound, miltefosine, has been used for the topical treatment of cutaneous metastasis in breast cancer. However, this drug exhibits gastrointestinal toxicity and hemolytic activity. We investigated miltefosine synthetic route as well as the synthesis of cycloalkyl analogues possibly less toxic and hemolytic. We started from miltefosine synthesis, which included four steps: a) generation of hexadecyl phosphorodichloridate; b) generation of 2-(hexadecyloxy)-3-methyl-oxo-1,3,2-oxazaphospholane; c) generation of hexadecyl 2-(methylamino) ethyl phosphate; d) production of the final product miltefosine (hexadecylphosphocholine). The route was optimized, resulting in the desired drug. After that, several methods for symmetrical diols monoprotection were investigated aiming at the generation of ω-hydroxydecyl cycloalkylmethyl ethers to be further employed in miltefosine synthetic route aiming at alkoxycycloalkyl analogues. Several attempts were realized however unsuccessfully, preventing us to move on in these analogues synthesis. In a different approach, we started from cyclohexylethanol and, employing the synthetic route of miltefosine, obtained the third intermediate, 2-cyclohexylethyl 2- (methylamino)ethyl phosphate pure. The methylation step, last one to obtain the cycloalkyl analogue, resulted in a dimethyl analogue instead of a trymethyl one. We believe that adjusting the reaction parameters, such as increasing reagents concentrations, should result in a successful methylation step. The intermediate obtained as well as the analogue planned might be future evaluated in terms of hemolytic potential and antitumor activity.

Os pacientes submetidos ao tratamento antineoplásico necessitam de um acesso venoso que permita a infusão segura das drogas quimioterápicas, evitando assim o risco do extravasamento. O extravasamento quimioterápico é definido como o escape de drogas do vaso sanguíneo para os tecidos circunjacentes, e seus efeitos tóxicos locais variam podendo causar dor, necrose tissular ou descamação do tecido. A morbidade depende do tipo da droga, da quantidade extravasada, da sua concentração, da localização do extravasamento, das condições do paciente e do intervalo entre o fato, seu reconhecimento e o tratamento. A prática baseada em evidências é uma abordagem que capacita os profissionais buscarem a melhor evidência para o cuidado, respeitando a opinião dos pacientes e seus familiares. O presente estudo é uma revisão integrativa da literatura, que teve como objetivo buscar e avaliar as evidências disponíveis na literatura sobre as intervenções eficazes frente ao extravasamento de drogas quimioterápicas vesicantes, em cateteres periféricos, prevenindo e minimizando lesões no paciente adulto oncológico. Para a seleção dos artigos utilizamos a base de dados Medline, e a amostra constituiui-se de 16 artigos. As medidas de prevenção do extravasamento são consideradas mais eficazes e recomendadas. Para o manejo do extravasamento das drogas doxorrubicina e epirrubicina é recomendado aplicação de gelo local, os antídotos dimetilsulfoxide tópico e dexrazoxane intravenoso, intervenção cirúrgica se houver persistência dos sintomas ou para grande quantidade de droga extravasada. Para o extravasamento de mitomicina C, gelo local e intervenção cirúrgica em lesões detectadas após 48 horas; para mecloretamina é indicado gelo e o antídoto tiossulfato de sódio. Para o manejo da vinorelbine é recomendado calor local e o antídoto hialuronidase por via subcutânea. As evidências extraídas dos estudos analisados podem auxiliar a implementação de cuidados de enfermagem eficazes relacionados ao extravasamento das drogas vesicantes contribuindo assim com a melhoria da assistência à saúde. / Patients submitted to antineoplastic chemotherapy need a venous access that allows for the safe infusion of chemotherapeutic drugs, thus avoiding the risk of chemotherapeutic extravasation. Chemotherapeutic extravasation is defined as the escape of drugs from the blood vessel to surrounding tissues. Its local toxic effects vary and can cause pain, tissue necrosis or flaking. Morbidity depends on the type of drug, the extravasated quantity, its concentration, the location of the extravasation, the patient s conditions and the interval between the fact and its recognition and treatment. Evidence-based practice is an approach that trains professionals to look for the best evidence for care, respecting the opinions of patients and their relatives. This study is an integrative literature review that aimed to look for and assess available evidence in literature about effective interventions in case of extravasation of vesicant chemotherapeutic drugs, in peripheral catheters, minimizing skin injuries of adult cancer patients. To select the articles, we used the database Medline, and the sample consisted of 16 articles. Extravasation prevention measures are considered as the most effective and recommended measures. To handle the extravasation of doxorubicin and epirubicin, the local application of ice is recommended, the antidotes topic dimethyl sulphoxide and intravenous dexrazoxane, and surgical intervention if the symptoms persist or if a large quantity of the drug has extravasated. For the extravasation of mitomycin C, local ice and surgical intervention in injuries detected after 48 hours; for mecloretamine, ice is indicated, as well as the antidote sodium thiosulphate. To handle vinorelbine, local heat is recommended, as well as the subcutaneous application of the antidote hyaluronidase. The evidence extracted from the analyzed studies can support the implementation of effective nursing care related to the extravasation of vesicant drugs, thus contributing to the improvement of nursing care.

No description available.

INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.

INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.

Some compounds, analogous to those found in naturally occurring systems, are found to possess chemotherapeutic activity. Some, in the form of their nucleoside or nucleotide derivatives, are valuable antimetabolites in that they may block normal RNA or DNA polymerisation, or may be incorporated into nucleic acids to form fraudulent, but not necessarily defective, polymers. Modification of natural ring systems, with a view to promoting chemotherapeutic activity is therefore of considerable interest; variation in the position and nature of the modification or ring substituent having a marked effect on chemotherapeutic activity. It is the purpose of this thesis to suggest methods for the facile synthesis of various uracils, pyrazoles and pyrazolo [3,4-d] - pyrimidines with alkyl, aryl and glycosyl substituents such that the nature of the ring substituents is easily varied. To this end a number of ethoxymethylene reagents were prepared which, by reaction with primary amines and hydrazines, would give acyclic intermediates capable of easy cyclisation into the uracil, pyrazole and pyrazolo [3,4-d] pyrimidine ring systems. Variation in the nature of specific substituents being determined by the choice of amine or hydrazine, other substituents being varied by modification of the original reagent.

Made available in DSpace on 2014-06-11T19:23:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-01-29Bitstream added on 2014-06-13T20:29:45Z : No. of bitstreams: 1 carmo_ca_me_botib.pdf: 354246 bytes, checksum: 4c9e96974ccabd93669458a1fdf56b19 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Os anabolizantes esteróides têm sido amplamente utilizados por profissionais e atletas de elite para melhorar sua aparência e habilidades atléticas. Além disso, eles apresentam um importante papel quimioterapêutico no tratamento de vários tipos de distúrbios metabólicos, homeostáticos e sexuais, em ambos os sexos. Tendo em vista que muitas drogas esteróides têm apresentado diferentes resultados considerando efeitos genotóxicos e mutagênicos, o objetivo desse trabalho foi avaliar o potencial genotóxico do hormônio nandrolona (deca-durabolin®) in vivo em células da medula óssea e do sangue periférico de camundongos, usando o teste do micronúcleo e o ensaio do cometa, respectivamente. Os animas receberam injeção intradérmica de 3 concentrações do hormônio esteróide (1.0, 2.5 e 5.0 mg/kg peso corporal). As células foram coletadas 24 h após o tratamento hormonal para o teste do micronúcleo (avaliação da clastogenicidade) e o teste do cometa (avaliação da genotoxicidade). O teste do micronúcleo evidenciou que as duas maiores doses testadas da nandrolona induziram aumentos estatisticamente significativos de células micronucleadas e o teste do cometa não evidenciou aumento significativo de danos no DNA nos linfócitos do sangue periférico. Sob estas condições experimentais, conclui-se que o hormônio esteróide nandrolona apresentou efeito clastogênico e/ou aneugênico e, por outro lado, não foram observados efeitos genotóxicos quando o mesmo foi administrado intradermicamente em camundongos / Anabolic androgenic steroids have been widely used by professional and elite athletes to improve their appearance and athletic abilities. Besides, they have an important place in the chemotherapeutic treatment of various types of metabolic, homeostatic, and sexual disorders in both sexes. Since many steroidal drugs have been found to be different results considering genotoxic and mutagenic effects, the aim of this study was to evaluate the genotoxic potential of nandrolone (deca-durabolin®) in vivo in bone marrow and peripheral blood cells of mice, using micronucleus and comet assays, respectively. The animals received intradermal injection of the 3 concentrations of the steroid (1.0, 2.5 and 5.0 mg/kg body weight). The cells were collected 24 h after the hormone-treatment for the micronucleus (clastogenicity endpoint) and comet assays (genotoxicity endpoint). Micronucleus test showed that the two higher tested-doses of the nandrolone induced statistically significant increase of the micronucleated cells and comet assay no evidenced significant increase in the DNA damage of the lymphocytes from peripheral blood. Under our experimental conditions, the nandrolone steroid hormone showed clastogenic and/or aneugenic effects and, on the other hand, no genotoxic effects when administered intradermally to mice