I have been intensively involved in the research on the application of currently available knowledge for the improvement of cancer care. This research covers the types of treatment that are appropriate for different clinical conditions (benchmarking and guidelines), planning services to improve access for patients, monitoring service delivery through patterns of care studies and development of the knowledge and skills of the cancer workforce. I devoted considerable effort to better educating the cancer workforce by measuring cancer teaching and developing model curricula and innovative teaching programs. I have made substantial contributions to knowledge about best practice by developing clinical practice guidelines and have developed tools and plans for cancer service delivery and have had a major influence on the training of the undergraduate and specialist medical workforce about cancer.

"April 2004" / Bibliography: leaves 121-142. / xviii, 142, [19] leaves : ill. (some col.), plates (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Attempts to build a complete understanding of the cellular mechanisms associated with gastrointestinal mucositis through investigations of the effects throughout the gastrointestinal tract of chemotherapeutic agents Methotrexate and Irinotecan, the possible ameliorating potential of the cytokine Interleukin-11 in reducing the side effects of chemotherapy, the expression of pro- and anti-apoptopic proteins and transcription factors along the gastrointestinal tract in normal human patients and the time-course of development of oral mucositis in human patients. Suggests that the entire gastrointestinal tract follows a similar pattern of development of mucositis. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2004

Second only to lung cancer, breast is the leading type of cancer among women in the US. Despite all the medical advances over the past few decades, toxicity and increased resistance to standard drug therapy still remains a significant problem. The heterogeneic nature of all cancers has led to a shift in treatment approaches, in that more research is being carried out with combination treatments in the hope that a multidirectional targeting of cancer will be far more effective than the current single treatment options. Our goal was to gain a better understanding of the molecular mechanisms of a nonhydrolyzable ether analog of RRR-[alpha]-tocopherol, 2, 5, 7, 8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (abbreviated [alpha] -TEA), and to investigate its efficacy when used in combination with known chemotherapeutics 9-nitro-camptothecin (9NC), and Paclitaxel (Taxol). The data presented here looks encouraging as it shows a clinically relevant delivery method using [alpha]-TEA and 9NC has the unique ability to reduce primary tumor burden as well as macro and micrometastatic lung and lymph node lesions in an aggressive syngeneic mouse mammary model, while displaying no obvious toxic side effects. The effect of combination treatments on tumor volume appears in part to be moderated by an increase in tumor cell apoptosis and a decrease in tumor cellular proliferation. Next, the intricate molecular mechanism of how [alpha]-TEA alone and in combination with 9NC is able to induce apoptosis in 66cl-4-GFP murine mammary cancer was investigated. The data suggest that the signaling pathway that ultimately leads to apoptosis is caspase dependent, is able to upregulate pro-death players while at the same time downregulate pro-survival proteins such as c-Flip and survivin. Finally, we investigated the efficacy of [alpha]-TEA used in an allograft mouse model following treatment with Taxol. Combination treatments were able to significantly reduce primary tumor burden, decrease lung and lymph node micrometastases, tumor cell proliferation, tumor blood vessel density as well as increase tumor cell apoptosis. Based on the results presented, we propose that [alpha]-TEA when used alone and in combination is an effective, non-toxic option for cancer treatment which warrants further investigation. / text

Oral mucositis is a common adverse side-effect caused by cancer treatments and can lead to mucosa toxicity. Patients with oral mucositis may experience extreme pain and may not be able to eat, drink and talk and, as a result, their quality of life is impaired. Thirty to eighty five percent of patients undergoing chemotherapy would develop oral mucositis. Preventing or reducing incidence of oral mucositis and its severity can help reduce patients’ sufferings. One of the methods to achieve this objective is the oral cryotherapy, which is a prophylactic intervention. However, there is no evidence-based guideline to instruct nurses on providing oral cryotherapy to cancer patients. The aims of this study are 1) to establish an evidence-based guideline on applying cryotherapy to reduce the incidence and severity of chemotherapy-induced oral mucositis, 2) to develop a standard nursing care and assess its transferability and feasibility, and 3) to develop a communication plan and evaluation plan for this guideline in an oncology ii- department for the targeted local hospitals in Hong Kong. A systematic search of four electronic journal databases identified seven articles corresponding to 6 randomized controlled trials (RCTs) on using oral cryotherapy for adult cancer patients. Five RCTs with high to weak quality reported supporting evidence for the beneficial effect of oral cryotherapy on chemotherapy-induced oral mucositis, whereas 1 RCT with moderate quality failed to identify supportive evidence for the use of oral cryotherapy. However, potential confounding factors were identified to be presented in that insignificant RCT. Hence, there was sufficient evidence to show that oral cryotherapy can significantly reduce chemotherapy-induced oral mucositis in adult cancer patients. An evidence based guideline for using cryotherapy on chemotherapy-induced oral mucositis in adult cancer patients was established. The transferability and feasibility of the proposed oral cryotherapy guideline were assessed. As identified, the clinical situation and patient characteristics in the local settings are similar to those who reported in the reviewed studies. Staff readiness, skills and resources are also readily available in the target clinical settings. Findings from the reviewed studies of oral cryotherapy can be transferred to the local target settings and are feasible to be implemented. It is also estimated that the innovated guidelines for cryotherapy can save HK$3,210,745 per year for the target setting. Stakeholders for the innovated guideline in the local setting were identified. And a communication plan was developed. A pilot study lasting for 10 weeks will be conducted to test the feasibility of the staff training session and the implementation of the oral cryotherapy guideline. Modification of innovated guidelines will be made after evaluating the data collected from the pilot study. Eventually, the final version of the evidence-based guideline will be established. A six months evaluation plan will be used to evaluate the implementation of the new guideline. The policy for adopting the oral cryotherapy will be determined with the outcome measures, including the incidence of chemotherapy-induced oral mucositis, mean of the oral mucositis score, staff satisfaction level, and the cost and benefit ratio of the innovated guideline. / published_or_final_version / Nursing Studies / Master / Master of Nursing

Discovery of anti-cancer cisplatin was a great success in anti-cancer chemotherapy. Numerous analogues of cisplatin such as carboplatin and oxaliplatin, were developed to improve the clinical effectiveness. Nevertheless, the clinical uses of these platinum-based drugs are limited by the occurrence of drug-resistance, narrow range of susceptible cancer types and severe toxicity. These drawbacks have stimulated the development of other metal-based compounds with distinct mechanisms of anti-cancer action. In this study, a series of ytterbium(III) porphyrin and iron(II) polypyridyl complexes were synthesized. Their anti-cancer activities were examined. With the aid of gene expression profiling and bioinformatics analysis, the mechanisms of these anti-cancer active complexes have been examined. A series of ytterbium(III) porphyrin complexes have been prepared and structurally characterized. An ytterbium(III) octaethylporphyrin complex (1) was found to exhibit potent anti-cancer activities with cytotoxic IC50 values down to sub-micromolar range. Complex (1) was shown to exist as a dimeric hydroxyl-bridged complex [Yb2(OEP)2(μ-OH)2] (where H2OEP = octylethylporphyrin) in CH2Cl2 and in solid state, and as monomeric [Yb(OEP)(DMSO)(OH)(OH2)] in DMSO/aqueous solution. Unlike various anti-cancer lanthanide complexes which are commonly proposed to target cellular DNA, our transcriptomics data, bioinformatics connectivity map analysis and cellular experiments altogether indicate that (1) exerts its anticancer effect through apoptosis which is highly associated with endoplasmic reticulum stress pathway. Two iron(II) polypyridyl complexes [Fe(qpy)(CH3CN)2](ClO4)2 (Fe-1a) (qpy =2,2’:6’,2”:6”,2’”:6”’,2””-quinquepyridine) and [Fe(Py5-OH)(CH3CN)](ClO4)2 (Fe-2a) (Py5-OH = 2,6-bis[hydroxybis(2-pyridyl)methyl]pyridine) were found to display selective cytotoxicity towards cancer cell lines over a normal lung fibroblast cell line. Affymetrix oligonucleotide microarray and bioinformatics analysis suggested that the anti-cancer mechanisms of Fe-1a and Fe-2a involve apoptosis, cell cycle arrest, activation of p53 and mitogen activated protein kinase (MAPK). Complex Fe-1a induced the formation of reactive oxygen species (ROS) in a concentration-dependent manner. Both iron complexes could cleave supercoiled plasmid DNA. The cellular DNA damage induced by both complexes was confirmed by comet assay and phospho-histone protein ( -H2AX) immunofluorescence assay. Cell cycle progression analysis revealed that Fe-1a induced both S- and G2/M-phase cell cycle arrests, whereas Fe-2a induced a G0/G1-phase arrest. Apoptosis induced by both complexes was confirmed by annexin-V/SYTOX green flow cytometry analysis and western blotting. Moreover, p53 and MAPK activation were found to be associated with the induced apoptosis. By employing the cationic porphyrin ligand, 5-(p-N-methylpyridyl)triphenylporphyrin [H2(5-MePyTPP)]+, a series of cationic metalloporphyrin complexes formulated as [M(porphyrinato)]n+ (where M = PtII, RuII, CoII or AuIII, n = 1 or 2) were prepared. The cytotoxicities of these complexes were examined. The platinum(II) and ruthenium(II) complexes were relatively non-cytotoxic towards the examined cancer cell lines with IC50 >24 μM. [CoII(5-MePyTPP)]Cl displayed a more pronounced anti-cancer activity with IC50 values between 7.48 – 17.7 μM. However, this Co(II) complex displayed poor selectivity towards the cancer cell lines compared to the normal cell line. The gold(III) porphyrin complex [AuIII(5-MePyTPP)]Cl2 showed a much higher potency (IC50 =3.01 -10.7μM) than the other [M(5-MePyTPP)]n+ prepared. By means of flow cytometry and fluorescence microscopy, [AuIII(5-MePyTPP)]Cl2 was found to induce G2/M-phase cell cycle arrest and necrotic cell death in HeLa cells. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Human mesenchymal stromal cells (hMSCs) are part of bone marrow micro-environment that supports hematopoiesis. However, hMSCs also enhance tumor progression and survival when they become part of the cancer micro-environment. I aimed to investigate the interaction between hMSCs and cancer cells during chemotherapy. Firstly, I studied the interaction between hMSCs and T-lineage acute lymphoblastic leukemia (T-ALL) cells under pegylated arginase I (BCT-100) treatment. Three T-ALL cell lines were sensitive to BCT-100 but not hMSCs. Conversely, hMSCs could partly protect all T-ALL cell lines from BCT-100 induced cell death under transwell co-culture condition. Concerning the possible mechanism, the intermediate metabolite L-ornithine could not rescue most T-ALL cells from BCT-100 treatment. But the downstream L-arginine precursor, L-citrulline could partly rescue all T-ALL cells from BCT-100 treatment. Ornithine transcarbamylase (OTC) converts L-ornithine into L-citrulline. OTC expression level in hMSCs remained relatively high during BCT-100 treatment but OTC expressions in T-ALL cell lines declined drastically. It suggested that hMSCs may protect T-ALL cells against BCT-100 treatment by having sustained OTC expression. Suppression of hMSCs by vincristine (VCR) disrupted the protective effect of hMSCs to most T-ALL cells during BCT-100 treatment. This suggests that by transiently suppressing hMSCs, we may abolish the protective effect of hMSCs to T-ALL cells during BCT-100 treatment. Then I studied the interaction between hMSCs and neuroblastoma under cisplatin treatment. Two neuroblastoma cell lines were used for both of them are cisplatin sensitive while hMSCs are cisplatin resistant. hMSCs could partly protect neuroblastoma cells from cisplatin induced cytotoxicity. On the other hand, exogenous IL-6 but not IL-8 could also partly rescue them from cisplatin induced cytotoxicity. IL-6 activated STAT3 phosphorylation dose-dependently and enhanced expression of detoxifying enzyme (glutathione S-transferase π, GST-π) in neuroblastoma. Such effect could be counteracted by anti-IL-6R neutralizing antibody tocilizumab (TCZ). However, TCZ failed to suppress hMSCs’ protection to neuroblastoma during cisplatin treatment. This suggests involvement of multiple factors. Up-regulation of serum GST-πin some hTertMSCs/neuroblastoma co-engrafted SCID mice compared to neuroblastoma engrafted mice provided a clue that GST-π might be a possible stromal-protection factor. Caffeic acid phenethyl ester (CAPE) is a known GST inhibitor after tyrosinase activation. Neuroblastoma cells expressed tyrosinase and CAPE enhanced cisplatin cytotoxicity on them, with or without hMSCs. Paradoxically, CAPE enhanced GST-πexpression with or without cisplatin treatment in neuroblastoma suggesting possible negative feedback to GST-π inhibition. However, such additive effect of CAPE to cisplatin cytotoxicity was not observed in vivo. Further delineation of the in vivo study design may help to verify the additive effect of CAPE to cisplatin cytotoxicity in vivo. Finally, I studied the effect of apoptotic cancer cells (AC) on the immune function of hMSCs. hMSCs could phagocytose apoptotic neuroblastoma cells with respective up-regulation of many immune-mediators including two highly-expressed cytokines IL-6 and IL-8. Up-regulation of these immune-mediators may enhance immune cells chemotaxis. Further detailed investigation on the effect of AC-engulfed hMSCs to other immune cells will help us to understand the dynamic interaction between cancer cells and stromal cells during chemotherapy. / published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Gliomas are the commonest type of primary malignant brain tumours of the central nervous system (CNS). The highly aggressive and infiltrative characteristics of gliomas render them one of the most lethal cancers. Amongst all, the most malignant form of glioma is glioblastoma multiforme (GBM), a World Health Organization (WHO) grade IV astrocytoma. Despite well-developed multimodal treatment including surgery, radiotherapy, and chemotherapy, the prognosis of GBM patients remains poor with median survival of just over one year. This high mortality rate is commonly the result of relentless tumour recurrence secondary to the tumour’s intrinsic resistance towards its standard chemotherapeutic agent temozolomide (TMZ). Prolyl 4-hydroxylase, beta subunit (P4HB) is an endoplasmic reticulum stress response (ERSR) chaperone protein that was previously found to be overexpressed in the chemoresistant glioma cell lines D54-MG and U87-MG. Differential expressions of numerous microRNAs (miRNAs) were also found between chemosensitive and chemoresistant glioma cell lines. As such, we surmised that the dysregulation of a P4HB-regulating miRNA may contribute to P4HB upregulation and therefore chemoresistance in glioma. MiR-210, a commonly dysregulated miRNA in various cancers, is one of the most highly downregulated miRNAs in chemoresistant glioma cells (compared to chemosensitive glioma cells), and, based on bioinformatics findings, may also regulate P4HB expression. MiR-210 was therefore selected for further investigations regarding its potential roles in glioma chemoresistance. The regulatory relationship between P4HB and miR-210 was subjected for verifications. With the use of quantitative real-time polymerase chain reaction (qPCR) and western blotting, the intrinsic expressions of P4HB and miR-210 were studied. The upregulation of P4HB in D54 and U87 chemoresistant glioma (compared to the parental) cell lines were found to correlate reciprocally with the downregulation of miR-210 in the same chemoresistant glioma cells. To delineate the potential regulatory role of miR-210, a gain of function approach was adopted. Transfection of a miR-210 mimic was performed into the D54 and U87 parental chemosensitive (D54-S and U87-S) and chemoresistant (D54-R and U87-R) cells, along with a negative control. The transfection efficiency of miR-210 as well as the subsequent P4HB expressions was verified. It was found that P4HB expression was downregulated as a result of miR-210 upregulation both at the mRNA and protein levels in glioma cells. Furthermore, the effects of miR-210 overexpression on chemoresistance in the glioma cells were tested by performing cell proliferation assay. Decrease in the half maximal inhibitory concentration (IC50) of TMZ were found in all cell lines overexpressing miR-210, suggesting that miR-210 upregulation may lead to P4HB inhibition, which would at least partially mediate an alleviation of glioma cells’ resistance towards its chemotherapeutic agent TMZ. In summary, miR-210 is downregulated in chemoresistant glioma cells in vitro. It plays a potential role in regulating P4HB expression, hence chemoresistance in GBM cells. Future investigations may focus on its mechanism of action and potentiality for therapeutic intervention. / published_or_final_version / Surgery / Master / Master of Medical Sciences

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published_or_final_version / abstract / toc / Molecular Biology / Doctoral / Doctor of Philosophy