PAPU has a wide range of effects on various immunological cells and functions.  It has been shown to enhance cellular and humoral immunity, in particular anti-cancer host defences, in both animals and man. In a small number of clinical trials (breast and stomach cancers) it appears to have a beneficial adjuvant effect, in terms of prolongation of disease free and overall survival. However, the most beneficial therapeutic regimen has yet to be established.  Previously, PAPU has been used in low doses (60 mg and 100 mg) in the post-operative period. This thesis was designed to evaluate the effects of a much higher dose of PAPU, given in the peri-operative period on both cellular and humoral immune responses in patients with breast cancer undergoing surgery. We have shown that PAPU stimulates the natural killer (NK) cell and lymphokine activated killer (LAK) cell activity. These cells are believed to play an important role in the host resistance against metastatic dissemination in patients with malignant disease and have also been reported to have substantial anti-tumour activity against a wide range of different types of tumour cells.  In addition, PAPU also enhanced the release of C-reactive protein (CRP) and associated cytokines [interleukin 1<span style='font-family: Symbol'>b (IL1<span style='font-family:Symbol'>b), interelukin 6 (IL6) and tumour necrosis factor <span style='font-family:Symbol'>a (TNF<span style='font-family:Symbol'>a)], as well as stimulated T lymphocytes in the peri-operative period.  CRP is believed to play a pivotal role in the host defences. In addition, an optimum immunomodulatory dose of PAPU has been defined by an in vitro analysis of natural cytotoxicity and mitogen response assays of peripheral blood mononuclear (PBM) cells in healthy volunteers. PAPU was used in a concentration of 1ul/ml, 10ul/ml, 100ul/ml, 250ul/ml and 500 ul/ml. 100ul/ml was noticed to produce maximum stimulation of NK and LAK cell cytotoxicity.

No description available.

No description available.

No description available.

The psychosocial intervention in cancer patient management has been shown to reduce anxiety effectively, but no assessment has been made of the effect on health related quality of life (HRQOL). The aims of this project were to examine head and neck cancer patient's level of information and assess anxiety level and HRQOL in an attempt to recommend the educational psychosocial support needed for oral and pharyngeal cancer patients. The first part of this research audits the patients' information support (as part of the psychosocial support) and preferred format for additional information material. A locally developed questionnaire was applied to three groups of oral disease patients the multidisciplinary team approach was significantly better in informing oral and pharyngeal cancer patients. The survey also confirmed the patients' preference for written format information materials and the low preference for the computer technology as a source for health information. The second part of the study aimed to assess oral and pharyngeal cancer patients' anxiety level and HRQOL. The results showed that patients have levels of HRQOL comparable to those previously reported in similar studies, although patients had higher level of anxiety. The third section correlates the anxiety scores from the HADS to HRQOL scores the HADS-Anxiety scores were significantly correlated to the SF-36 scores at the preoperative stage and to the EORTC H&N35 scores at the postoperative stages. Predictability equations were formulated for the HRQOL domains scores using the HADS score. The final section was a semi-structured interview with 30 head and neck cancer patients and their families. This was a cross sectional study with the aim of examining the relationship between information, educational level, anxiety and HRQOL. In conclusion, oral cancer patients required more sophisticated gating of information about disease management. There was a significant correlation between anxiety scores with HRQOL scores however the high anxiety scores suggested that patients' education should include methods of anxiety control. Patients' perception of good psychosocial support can improve their HRQOL.

Cytotoxic chemotherapy remains the mainstay of treatment for patients with cancer, however immunotherapy is starting to emerge as an additional modality of treatment. Evidence suggests that chemotherapy can synergise with immunotherapy to improve responses. Although CD8 T cells have been regarded as the main anti-tumour effector cell, the role of CD4 T cells in orchestrating CD8 and other anti-tumour responses is increasingly recognised. However, the CD4 T cell population contains effector and suppressive subsets with diverse and opposing functions. This thesis describes the establishment of a murine mesothelioma model with which to study the effects of different CD4 subsets on anti-tumour immune responses, and investigate their capacity to provide cognate help to tumour antigen specific CD8 T cells. Haemagluttin (HA) specific CD4 T cells from transgenic mice were polarised in vitro into Th1, Th2, Th17 and Treg subsets and adoptively transferred alongside HA specific CD8 T cells into mice bearing HA expressing tumours derived from a mesothelioma cell line. The effects of the different CD4 subtypes on tumour growth and their capacity to provide ‘help’ to CD8 T cells was investigated in a prophylactic treatment model and in the context of treatment with gemcitabine chemotherapy. Results showed that survival and behaviour of in vitro differentiated CD4 subtypes after adoptive transfer was highly variable and that only Th1s displayed anti-tumour activity when injected prophylactically, prior to tumour inoculation. Cytotoxic chemotherapy did not provide a favourable environment for adoptive transfer of in vitro differentiated CD4 cells. No antitumour activity was seen against established tumours, which may have been due to overriding tumour induced immunosuppressive mechanisms. Successful treatment of established tumours that had been treated with chemotherapy required both the provision of HA specific CD8 cells and the prior removal of an established, endogenous regulatory CD4 T cell population.

The type 1 insulin-like growth factor receptor (lGF-1 R) plays a significant role in tumor growth and spread, and IGF-1 R inhibitors and antibodies are now undergoing clinical testing. However, factors that regulate sensitivity to IGF-1 R inhibition remain unclear. The aim of this project is to identify proteins whose depletion regulates sensitivity to IGF-1 R inhibition, in order to design effective combination treatments to benefit patients. An IGF-1 R kinase inhibitor, AZ12253801 (provided by AstraZeneca) was able to block IGF-induced phosphorylation of IGF-1 R in DU145 prostate cancer and MCF-7 breast cancer cells, inhibited downstream signalling in DU145 cells, and also inhibited proliferation and cell survival of both cell lines. AZ12253801 was used in an unbiased siRNA screen in both cell lines, using two s'iRNA libraries (779 kinase-related Kinome and 230 DNA repair-associated siRNAs). Eight Kinome and five DNA repair-associated hits have been identified after primary and second round screens, and further validated. The strongest hit was dishevelled homolog 3 (DVL3), a member of the WNT signalling pathway, which is highly expressed in both cell lines. DVL3 silencing caused reduction in active l3-catenin and inactivated the mTOR pathway, consistent with previous studies, and did not affect IGF-1 Rand AKT activity. However, DVL3 silencing led to activation of MEK1/2-ERK1/2 in serum-starved cells and sensitized this pathway to IGF-1 stimulation, with translocation of ERK1/2 into the nucleus and increased expression of ERK1/2 target genes. A DVL PDZ domain inhibitor (DVLi) showed similar effects on active l3-catenin, mTOR signalling and ERK1/2 signalling activity. The administration of DVLi increased sensitivity to AZ12253801 in cell lines with detectable ERK1/2 activation, but not prostate cancer cells in which ERK signalling was suppressed and AKT was activated in the context of loss of functional PTEN. Furthermore, DVL3 regulated activation of ERKs by influencing signaling downstream of the IGF-1 R and upstream of RAS, and DVL3 was found in a complex with the adaptor proteins GRB2 and DAB2. GRB2 knockdown was capable of abolishing ERK1/2 activation induced by DVLi, further implicating involvement of GRB2, and DAB2 silencing sensitized to IGF-1 R inhibition, mimicking effects of DVL3 depletion. Taken together, DVL3 silencing or inhibition enhances sensitivity to IGF-1 R inhibition by negatively regulating the ERK1/2 signaling pathway. These investigations shed new light on the factors that regulate IGF signaling, and provide a rational basis for design of clinical trials of IGF-1 R inhibitors.

Bibliography: leaves 159-194 / xi, 194 leaves, [3] leaves of plates : ill. (2 col.) ; 31 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1986

Many anticancer therapies, including radiotherapy, act by damaging the deoxyribosenucleic acid (DNA) that is fundamental to cell function and proliferation. H2AX is a histone protein associated with DNA that is phosphorylated to produce γH2AX in response to DNA double strand breaks (DSBs), the most lethal lesions caused in cancer cells. This thesis examines the translation of γH2AX detection assays to clinical situations in order to provide biomarkers of response that might help to guide the treatment of cancer patients. γH2AX immunohistochemistry was developed in preclinical xenograft models, and validated over a range of radiation doses and over time after irradiation. The method was prepared for translation to archived clinical biopsy and surgical specimens. The DSB Biomarkers Pilot Study was established in order to develop a method for γH2AX quantification in direct tumour cell specimens obtained using the clinical technique of fine needle aspiration (FNA) cytology. Eleven patients undergoing anticancer therapy were recruited to the study, and the method evaluated. The coefficient of variation of the measure was 49%. Non-invasive imaging for γH2AX would allow DNA damage to be quantified in all tumour sites, and on multiple occasions. An antibody-based nuclear medicine imaging agent was re-engineered using Fab fragments of the antibody. The novel agent demonstrated improved pharmacokinetics when compared to the whole antibody agent, but reduced target specificity. The findings further develop the potential to exploit DNA damage biomarker measurements in clinical oncology.

High Intensity Focussed Ultrasound (HIFU) ablation is a promising technology for the non-invasive, targeted treatment of certain types of cancer. The technique functions by subjecting tumours to a cytotoxic level of intense, localised heating, while leaving the surrounding tissue unharmed. However, a number of limitations in the available HIFU treatment monitoring methods are currently hampering the effectiveness and clinical adoption of the therapy. This work aims to develop improved metrics of HIFU-induced biological damage that are specifically suited to monitoring and controlling HIFU ablation. Firstly, an optical method that enables straightforward quantification of thermal damage in protein-embedding hydrogels is developed. Secondly, hydrogels embedded with different cell lines are used to assess the performance of common temperature-based metrics of cell death across a range of HIFU-relevant conditions. Finally, a novel, passive acoustic detector designed for the real-time monitoring of HIFU-induced tissue damage is proposed. The detector is shown to predict lesioning with over 80% accuracy in regimes that are very likely to create lesions (60 J of acoustic energy or more), with an error rate of less than 6% for exposures that are too short to cause lesioning (up to 1 s long). The proposed detector could therefore provide a low-cost means of effectively monitoring clinical HIFU treatments passively and in real time.