No description available.

The effect of Marinol, which contains the antiemetic tetrahydrocannabinol (THC), was evaluated in five cancer patients undergoing chemotherapy. Subjects rated their nausea and vomiting, food intake, appetite and mood status three times daily. Drug therapy (THC) or no drug was administered for an average of four months during the course of their chemotherapy regimen. Subjects began taking THC the first day of chemotherapy and continued (5mg/three times a day) for an average of two weeks. Subjects reported their nausea and vomiting to be increased while receiving THC which coincided with their period of chemotherapy treatment. Subjective ratings for food intake and appetite varied in each case and did not always correlate with actual caloric intake from food. Food intake in most subjects was approximately the same, or greater with THC even though the period when THC was given coincided with chemotherapy treatment, and the use of emetigenic drugs. This resulted in weight maintenance or minor weight loss in most subjects. The absence of THC during chemotherapy treatment resulted in decreased food intake. Some of the moods reported most frequently by subjects while receiving THC were activity, interaction, and relaxation. Depression, social withdrawal, and anxiety were reported less frequently and usually occurred around the time of chemotherapy. The majority of the moods reported indicated that subjects had positive feelings associated with THC therapy. The results of this study indicated that THC benefitted cancer patients by increasing food intake during chemotherapy regimens without causing adverse behavioral changes. / Master of Science

Taxol®, an important anticancer drug, was first isolated in extremely low yield from the bark of the western yew, Taxus brevifolia. The clinical utility of Taxol has prompted a tremendous effort to obtain this complex molecule synthetically. Due to the chemical complexity of Taxol, its commercial production by total synthesis is not likely to be economical. Another natural product, 10-deacetyl baccatin III, is readily available in higher yield. Several methods have been reported for the synthesis of Taxol by coupling baccatin III and the N-benzoyl-β-phenylisoserine side chain. A new method for the synthesis ofTaxol from baccatin III is reported, and this method is compared with other methods. / Master of Science

The natural product, paclitaxel, has made tremendous contributions in supplying the arsenal of anticancer therapeutics, and was FDA approved for clinical use in 1992. In order to design simplified analogs, the conformation that paclitaxel adopts when binding to tubulin has been the subject of ongoing studies. Much evidence has led to a T-taxol proposal and a C3' constrained analog has been designed and synthesized as a test of this conformation. In the search for more active analogs, a number of modifications have been made to paclitaxel by other researchers. However, the nature of the alterations, and combinations thereof, have not been exhausted. To this end, synthesis of northern hemisphere B-ring analogs is underway. / Master of Science

No / Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT3) antagonist and a corticosteroid. The neurokinin-1 (NK1) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT3 antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK1 antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT3 antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK1 antagonist occurred within the first 8¿12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT3 antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8¿12 h following cisplatin-based chemotherapy, after which time substance P acting at NK1 receptors becomes the dominant mediator of vomiting.

Yes / -

Investigations concerning the cellular response of tumor tissue to treatment with dimethyl sulfoxide and hematoxylin have not been reported. To establish the response of neoplastic tissue and cells to this combination of agents, this study was undertaken to determine the effects of dimethyl sulfoxide and hematoxylin on a transplantable lymphosarcoma in mice.

Made available in DSpace on 2014-06-11T19:31:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-08-13Bitstream added on 2014-06-13T21:02:08Z : No. of bitstreams: 1 behling_eb_dr_arafcf.pdf: 524574 bytes, checksum: 4282566c71831604413ca31e88390247 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / As crianças com câncer necessitam manter o crescimento linear e o ganho de peso para uma melhor evolução clínica. Assim, o tratamento da criança com câncer deve garantir não só sua sobrevivência, mas proporcionar crescimento e desenvolvimento adequados. A avaliação nutricional é utilizada para reconhecer o paciente com maior facilidade de desenvolver a má nutrição garantindo assim um planejamento nutricional adequado. O objetivo do presente estudo foi avaliar o estado nutricional de crianças antes, durante e após o tratamento quimioterápico. Foram avaliadas 14 crianças com câncer, com idade entre 5 a 15 anos, divididas em dois grupos: Grupo Tumores Sólidos e Grupo Tumores Hematológicos. Estas foram avaliadas através dos dados de ingestão alimentar, antropometria, análise por Impedância Bioelétrica (BIA) e por Diluição Isotópica. Os resultados encontrados demonstram que os pacientes apresentaram um aumento de peso, estatura, índice de massa corporal, circunferência do quadril, da cintura e do braço, da prega cutânea subescapular, assim como o aumento da massa gorda pela técnica de diluição isotópica durante o tratamento quimioterápico, no Grupo Tumores Hematológicos. No Grupo Tumores Sólidos as crianças apresentaram uma diminuição da massa magra, quando analisado pela impedância bioelétrica. Houve uma correlação positiva entre a prega cutânea tricipital e a massa gorda obtida através da BIA e pela Diluição Isotópica. A circunferência muscular do braço também se correlacionou com a massa magra estimada pela BIA e pela Diluição Isotópica. Não houve mudança na ingestão energética e de macronutrientes nos três momentos da pesquisa. Esses resultados demonstram que os pacientes com tumores hematológicos apresentaram aumento de peso, estatura e de massa gorda, fato este não ocorrido no Grupo Tumores Sólidos. / Children with cancer need to maintain growth and weight gain to a better clinic evolution. So, the treatment of children with cancer must not only guarantee the survival but also adequate growth and development. The nutritional assessment is useful to recognize the patient who is more accessible to develop malnutrition leading to an adequate nutritional plan. The aim of this study was to assess the nutritional status in children before, during and after chemotherapy treatment. In this study, 14 children with cancer were evaluated ranging from 5-15 years old devided into two groups: Hematologic Tumor Group and Solid Tumor Group. They were evaluated through dietary intake, anthropometry, bioimpedance analysis (BIA) and isotopic dilution. The results show that the patients increase weight, stature, body mass index, hip, waist and arm circumferences, subscapular skinfold thickness, as well as an increase in fat-mass with isotopic dilution technique during the chemotherapy treatment, in the Hematologic Tumors Group. In the Solid Tumor Group the children showed a reduction in fat free mass when assessed by bioelectric impedance. There was a positive correlation between triceps skinfold thickness and fat-mass with BIA and Isotopic Dilution technique. The arm muscle circumference correlated with the fatfree- mass estimated by the BIA and Isotopic Dilution. There was no change in energetic intake and macronutrients at the three moments of the research. These results demonstrate that patients with hematologic tumors had an increase in body weight, stature and fat-mass, which was not observed in Solid Tumors Group. The good correlation between anthropometry and isotopic dilution technique and BIA show its applicability in clinical practice.

Mucositis refers to the widespread damage of mucosal surfaces throughout the length of the alimentary tract (AT) that can occur during cancer treatment. Its development is an important clinical problem that complicates and limits treatment options as well as adversely affecting the quality of life and treatment outcomes for patients. Recent studies directed at determining the pathobiology of mucositis have indicated increasing evidence for the role of transcription factors, such as nuclear factor-κB (NF-κB), and certain pro-inflammatory cytokines, for example tumour necrosis factor (TNF), interleukin-1β (IL-1β) and interleukin- 6 (IL-6), in its development. This thesis developed from an initial clinical investigation in which the expression of NF-κB and COX-2 in oral mucosa was investigated in patients undergoing chemotherapy. Increased levels of NF-κB were demonstrated in the buccal mucosa following chemotherapy. It is well established that mucositis occurs in different sites of the AT. The aims of this research, therefore, were to compare and contrast the changes that do occur at different sites of the AT following chemotherapy in an established animal model (Dark Agouti (DA) rat). Furthermore, the studies were conducted to determine whether changes in tissue and serum levels of NF-κB and pro-inflammatory cytokines occurred following chemotherapy and, with respect to tissue levels, identify whether there were differences in expression at different sites throughout the AT. The final aim was to examine whether the histological changes and changes in pro-inflammatory cytokines were affected by the type of chemotherapy drug used. The effects of three chemotherapy drugs with different mechanisms of action (irinotecan, methotrexate and 5-fluorouracil) were investigated, all of which can cause mucositis in the clinical setting. The thesis is divided into a Literature Review (Chapter 1) followed by 4 research papers: Chapter 2 – “Nuclear factor- κB (NF- κB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy” Chapter 3 -“Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: Implications for the pathobiology of mucositis” Chapter 4 – “Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered?”, Chapter 5 – “Serum levels of NF-κB and pro-inflammatory cytokines following administration of mucotoxic drugs”. Chapter 6 provides an overall summary and discussion of the results. Previous research has indicated that following administration of chemotherapeutic agents there may be subclinical changes occurring in the mucosa prior to obvious clinical manifestations. The results presented in this thesis also demonstrate this in both humans and animals following administration of chemotherapy. Immunohistochemical analysis of tissue taken from the oral cavity, jejunum and colon from the DA rats following chemotherapy demonstrated that changes in NF-κB and the pro-inflammatory cytokines, TNF, IL-1β and IL- 6, occurred at all sites over a 72 hour time period. This was evident before severe histological evidence of mucositis were observed such as epithelial atrophy in the oral mucosa, atrophy, blunting and fusion of the villi in the jejunum and crypt ablation in the jejunum and colon. Furthermore, each of the three drugs caused different patterns of NF-κB and pro-inflammatory cytokine expression in the tissues; in spite of this, however, histological features of damage were similar. With respect to serum levels of NF-κB and pro-inflammatory cytokines, differences were observed between the serum and tissue levels. Generally, serum changes followed initial histological changes in the tissues, or occurred simultaneously with histological changes. The mechanisms behind this are unclear; however it may be that elevated cytokines in the tissues “overflow” into the serum as tissue damage increases. Furthermore, the use of serum cytokine level measurement to predict mucosal damage is limited because of the differences in timing and short time intervals between changes in the serum and tissues. This thesis has provided additional important information on mucositis pathobiology and highlights its complexity. In particular, it has provided new evidence supporting the notion that mucositis is not restricted to the oral cavity and that other sites of the AT are also affected. Furthermore, these results confirm previous data indicating that subclinical changes occur in the mucosa prior to the development of obvious histological damage or clinical manifestations of mucositis. Contrary to previous reports, these studies have indicated that, although the clinical and histological changes may be similar, the alterations in NF-κB and pro-inflammatory cytokines in the tissues are affected by the type of drug used. This has important implications in the management and prevention of mucositis in the clinical setting particularly when multi-drug or chemotherapy-radiotherapy regimens are used. A common pathway that leads to mucosal damage is yet to be determined. The fact that serum levels appear to reflect the “global” nature of the effects of chemotherapy, highlights the fact that ongoing research needs to be directed, not necessarily at specific side effects, but rather how side effects of chemotherapy are interrelated so that better patient management can be achieved and ultimately provide optimum treatment and better survival for patients with cancer. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1321557 / Thesis (Ph.D.) -- University of Adelaide, School of Dentistry, 2008

Insensitivity to chemotherapy is an ongoing issue in cancer treatment, one that appears to be highly dependent on patient-specific variations. It has been shown clinically that while a subset of patients will successfully respond to a particular chemotherapeutic regimen, there exists another subset of patients who when exposed to the same course of therapy will remain resistant to treatment or exhibit signs of relapse after treatment has been administered. This discrepancy raises interesting questions regarding the role that patient-specific variations play in controlling the efficacy of chemotherapy treatment regimens. Doxorubicin (Dox) is a common chemotherapeutic agent used in the treatment of a variety of solid tumors and leukemias and resistance to Dox treatment is a major issue in cancer chemotherapy, oftentimes leading to patient relapse. To gain a deeper understanding of the processes that influence Dox resistance, we must first understand the mechanisms that underlie and contribute to Dox's toxicity. To this end, the metabolic reactions that activate Dox have been implicated as major determinants of Dox cytoxicity and as possible factors that control Dox resistance in cancer cells. There are several lines of evidence that redox-dependent metabolism plays a large role in Dox toxicity. The Dox bioactivation network is comprised of a system of reduction/oxidation (redox) reactions that lead to the formation of toxic Dox metabolites and reactive oxygen species (ROS). Moreover, multi-drug resistant acute lymphoblastic leukemia cells derived from relapsed patients have elevated levels of the antioxidant glutathione and show insensitivity to Dox treatment. The redox dependence of Dox bioactivation, the understanding that Dox treatment generates ROS, and the evidence that Dox resistant cells exhibit increased antioxidant capacity, suggest the possibility that redox pathways modulate the efficacy of Dox treatment in cancer cells. The overall objectives of the proposed dissertation, therefore, were to investigate how the redox properties of the Dox bioactivation network influence Dox toxicity in acute lymphoblastic leukemia cells, and to provide evidence that cell-specific variations in the intracellular levels of these redox components influences the degree to which Dox treatment will induce cancer cell death. The significant findings of this study are that the redox reactions involved in Dox metabolism are dual-natured, containing a toxicity-generating module characterized by nicotinamide adenine dinucleotide phosphate (NADPH)-dependent Dox reductive conversion, as well as an ROS signal-generating module characterized by NADPH- and oxygen-dependent Dox redox cycling. The balance between the coupled redox reactions that comprise the toxicity- and ROS signal-generating modules of Dox bioactivation determines the sensitivity-phenotype of leukemia cells and phenotypic changes in the Dox-sensitivity of leukemia cells can be induced by the successful modulation of the Dox bioactivation network through the pharmacological inhibition of NADPH in a concentration- and cell type-dependent manner. This study highlights the importance of the intracellular redox network in controlling chemotherapy-induced ROS. The unequal distribution in antioxidant burden across the various intracellular antioxidant enzymes suggests a significant role for NADPH supply, as controlled by the enzyme glucose-6-phosphate dehydrogenase (G6PD), to the intracellular ROS buffering capacity of cells during instances of oxidative stress. Changes in G6PD activity were shown to promote protein-S-glutathionylation during oxidative stress conditions, thereby implicating G6PD in the modulation of redox-sensitive signal transduction pathways. The intracellular glutathione redox balance, a measure of the intracellular redox environment, can effectively regulate Dox-induced NF-κB signal transduction in leukemia cells. The systematic modulation of intracellular glutathione redox balance in leukemia cells by N-acetylcysteine (NAC) revealed an important role for protein S-glutathionylation mechanisms in the control of NF-κB signal transduction induced by Dox treatment. These findings identify the glutathione redox network as a potential therapeutic target for the systematic modulation of Dox sensitivity in cancer cells and elucidate the complex role that antioxidants such as NAC can play in modulating the effectiveness of Dox chemotherapy treatment regimens. Lastly, this study highlights the need for and the capacity of computational models to accurately describe the complex redox-reactions that contribute to Dox metabolism in leukemia cells. This study is groundbreaking in its use of computational modeling to analyze reversible electron transfer events between proteins using mass-action kinetics. The models developed in this study can accurately explain cytosolic doxorubicin bioactivation, intracellular hydrogen peroxide clearance, and kinase-specific S-glutathionylation, thereby showing that the use of comprehensive and/or relatively simple computational models can provide semi-quantitative predictions about the behavior of redox systems in mammalian cells as they relate to Dox-induced toxicity and Dox-induced cell signaling.