Multidrug resistance (MDR) describes the phenomenon whereby cancer cells exposed to a single cytotoxic drug develop cross resistance to numerous other structurally unrelated chemotherapeutics. The development of MDR is a major cause of cancer chemotherapy treatment failure in all types of cancer. Numerous mechanisms of MDR have been elucidated which include ATPbinding cassette (ABC) transporter proteins, cytoplasmic vaults, alterations in topoisomerase II and increased expression of glutathione-S-transferases, all of which result in reduced chemotherapeutic efficacy. Superficial bladder cancer is commonly treated with adjuvant intravesical chemotherapy using mitomycin C or epirubicin (an anthracycline), following surgical resection. However, despite this treatment, the recurrence rates of these tumours can approach 60%. This high recurrence rate represents the development of MDR in many cases. Previous work using anthracycline fluorescence has shown that MDR cells have reduced levels of anthracycline uptake and also demonstrate a characteristic nuclear sparing of drug uptake. This nuclear sparing phenomenon in MDR cells transcends tissue type and suggests that the nuclear membrane may also play a role in MDR. The work described herein discusses the current role of chemotherapy in the treatment of superficial bladder cancer, mechanisms of MDR and the role of the nuclear membrane in MDR. Following this our investigation of the role of the nuclear membrane is described, using a number of novel techniques including cell fusion and microinjection. In addition, we investigated MDR modulation by verapamil, with analysis of changes in cellular, cytoplasmic and nuclear drug uptake mediated by this known MDR reversing agent.

The aim of the study was to determine whether and to what extent mindfulness-based stress reduction (MBSR) has any effect on mood, disease related quality of life, wellbeing and endocrine symptoms in women with stages 0 to III breast cancer. The study chiefly used a randomised controlled trial design. Eligible participants had previously attended a day centre, Breast Cancer Haven in London, which offers support, information and complementary therapies for women. Eligibility was based on ending hospital treatment for breast cancer no less than two months and no more than two years previously (N=229). Consenting participants were randomly assigned to either an immediate intervention or wait-list control group. Participants completed the Profile of Mood States (POMS) (primary outcome measure), Functional Assessment of Cancer Therapy –Breast (FACT-B) and –Endocrine (FACT-ES), including their trial outcome indices (TOI) and World Health Organisation Five-Item Wellbeing Questionnaire (WHO-5) as well as a short proforma to obtain qualitative data. Two hundred and fourteen women, (mean age 49 years) completed the study, (a 93% response rate). Intention-to-treat between-group analysis showed that after the intervention, participants in the MBSR group, compared to controls, had statistically significantly improved scores on POMS Total Mood Disturbance at both eight weeks with MBSR group mean (SD) of 30.02 (31.60) compared to controls 47.81(39.81) (95% CI for difference -27.44 to -18.14, p<0.001) and 12 weeks mean (SD) of 29.83 (34.19) compared to controls 45.43 (35.51) (95% CI -25.01 to -6.20, p<0.001). Significant improvements were also found on all POMS subscales – anxiety, depression, anger, vigour, fatigue and confusion. Significant improvements were also found on a range of FACT dimensions: FACT-B, -ES, -B TOI, -ES TOI, and physical, emotional and functional wellbeing subscales, as well as on the WHO-5 Wellbeing Questionnaire. Qualitative findings revealed that participants found themselves to be more mindful and key themes included being calmer, centred, at peace, connected and more confident; being more aware; coping with stress, anxiety and panic; and accepting things as they are, being less judgemental of myself and others. The generalisability of these findings will be limited to those women attending Breast Cancer Haven with stages 0 to III breast cancer. MBSR was effective in improving mood state, quality of life including endocrine symptom and wellbeing in female breast cancer survivors (diagnosed with stages 0 to III breast cancer).

A barrier to assessing the effectiveness of respiratory physiotherapy has been insufficient accurate, reliable and sensitive outcome measures. Lung sounds provide useful, specific information for assessing and monitoring respiratory patients. However, standard auscultation techniques are too subjective to allow them to be used as an outcome measure. In this research, Computer Aided Lung Sound Analysis (CALSA) was used to assess whether adventitious lung sounds’ characteristics could be quantified clinically and used as a new objective, non-invasive, bedside clinical outcome measure for physiotherapy alveolar recruitment and airway clearance techniques. Two experimental studies were conducted incorporating ‘before-and-after’ and ‘repeated measures’ components. Fifty four participants with productive lung disorders (cystic fibrosis and bronchiectasis) were recruited from out-patient clinics. Demographic, anthropometric, lung function, oxygen saturation, breathlessness and lung sound data were collected at baseline and after a single intervention (selfintervention in the first study and intervention applied by a physiotherapist in the second study). The intra-subject reliability of crackle frequency (f) within each session was found to be ‘good’ to ‘excellent’, estimated by the Analysis of Variance, Intraclass Correlation Coefficient, Smallest Real Difference and Bland and Altman 95% limits of agreement. Crackle initial deflection width (IDW) and crackle two cycles deflection width (2CD) were reliable over short time periods. The f of crackles increased in the majority of participants post interventions. Agreement on the number (N) and timing (T) of crackles between CALSA and a physiotherapist‘s auscultatory findings was found to be poor in anterior chest sites, but higher in posterior sites. Conclusion: the use of CALSA to identify the type and f of adventitious lung sounds collected clinically is feasible; crackle IDW and 2CD are both reliable measures but crackle 2CD is more consistent; crackle f was more responsive than the N or T of crackles per breathing cycle to the interventions. In future, CALSA may provide an objective and responsive tool for assessing and monitoring respiratory interventions in clinical settings.

A detailed review of the literature revealed that children report mixed views towards ADHD and medication. They are also reported to experience a lack of control over their symptoms and in turn, report a reliance on medication to control behaviours. Research into children’s sense of self is conflicting, where studies reveal poor self-image, but other work confirms an inflated sense of self. In addition, differences between adult and child perceptions of ADHD exist, and are explained by the Attribution Bias Context (ABC) model which describes the nature of informant discrepancies. Gaining a greater understanding of children’s perceptions of ADHD is important in identifying and implementing effective interventions for children and their families. This qualitative study explored 5 children’s perceptions of ADHD through interview and drawing. Children’s teachers were also interviewed in order to explore discrepancies. Analysis of the data revealed a grounded theory of internalisation of the ADHD label for children, and difference for teachers. Children were found to experience ADHD emotionally, in on/off conditions, as a medical disorder, with external locus of control and as part of their self/identity. Medication was felt to control their behaviour. Teachers described children’s ADHD using a medical discourse and strengths were identified as attributes which are present in the absence of ADHD symptoms. Results are discussed in terms of similarities and differences between adult and child perspectives, and only some of the data supports the predictions of the ABC model. Implications of the findings are discussed in terms of academic and applied settings, and future research directions are considered with particular reference to exploration of the process of internalisation of the ADHD label.

In the mid 1990's the UK government began to focus on problem heroin use mainly as a drug related crime issue, and so attracting and retaining clients became a treatment priority. The concept of flexible prescribing, matching individual clients to treatment programmes appropriate to their drug using history and circumstances, began to gain support amongst politicians and clinicians. As part of this shift in emphasis, prescribing heroin to heroin addicts re-emerged as a treatment option. Injectable (and smokable) diamorphine (pharmaceutical heroin) began to be prescribed in a small number of drug dependency units under the direction of local psychiatrists, including two in North West England. One hundred and thirty three registered drug users were interviewed between August 1995 and February 1997 using a structured questionnaire. Three key areas and their association with heroin substitution prescribing were addressed; levels of criminal activity, levels of illicit drug use, and a range of client held perceptions and attributions regarding coping/quality of life. The mean age of the sample was 30 years, and 75% were male. 61% had used illicit heroin in the past month, spending on average £638, on a habit of 4g per week. Clients were subdivided on a number of variables and comparisons were made between groups according to (IV) prescription type (which drug), and form (injectable/smokable/oral mixture). Significant differences were found across each of three key variables, including differing levels of illicit drug use according to prescription form, and differing levels of specific criminal activity according to prescription type. Significant effects included; Clients on prescriptions which included ampoules were significantly more likely to report being able to cope with life, and spent significantly less time on drug taking activities, than those clients receiving other prescriptions. Clients on prescriptions which included `reefers' (smokable) reported significantly less shop lifting than clients receiving other prescriptions. It was concluded that the available empirical evidence regarding heroin prescribing is limited, and although some clinicians are yet to be convinced, it seems heroin does have its merits as a viable treatment option. Issues of cost and possible dispersion remain, and are discussed in relation to the continuing development of substitution treatment policy in the UK.

The purpose of this thesis was to examine the nature of executive function deficits in ecstasy users, and the contribution of these executive functions to performance on other cognitive tasks. Using recent theoretical models of executive functioning recreational ecstasy-polydrug users were tested in laboratory settings on measures of mental set switching, response inhibition, memory updating and access to semantic memory. It was found that ecstasy users performed significantly worse than nonusers on measures of updating and access, although cocaine also emerged as an important factor in deficits in access. The contribution of access and updating to performance on more complex executive function tasks was then assessedI.t was found that while associative learning is relatively independent of access and updating, the same was not true for everyday memory and syllogistic reasoning. Ecstasy group related deficits in syllogistic reasoning were slightly attenuated following control for access and substantially following control for updating. It emerged that everyday memory deficits were more related to the use of cannabis than the use of ecstasy. The results of this thesis have serious implications for those who use ecstasy and should be used in educating such individuals. Outside the area of Psychopharmacology this thesis provides further support for the nature of executive functions and their relationship with syllogistic reasoning and everyday memory. Future research should assess executive functions along the same paradigm and seek to recruit polydrug control groups.

Hypertension (HTN) is a major risk factor for cardiovascular diseases including stroke, coronary heart disease (CHD), chronic renal failure, peripheral vascular disease, myocardial infarction, congestive heart failure and premature death. The prevalence of HTN in Scotland is very high and although a high proportion of the patients receive antihypertensive medications, blood pressure (BP) control is very low. Recommendations for starting a specific antihypertensive class have been debated between various guidelines over the years. Some guidelines and HTN studies have preferred to start with a combination of an antihypertensive class instead of using a single therapy, and they have found greater BP reductions with combination therapies than with monotherapy. However, it has been shown in several clinical trials that 20% to 35% of hypertensive patients could not achieve the target BP, even though they received more than three antihypertensive medications. Several factors were found to affect BP control. Adherence and persistence were considered as the factors contributing the most to uncontrolled hypertension. Other factors such as age, sex, body mass index (BMI), alcohol intake, baseline systolic BP (SBP), and the communication between physicians and patients have been shown to be associated with uncontrolled BP and resistant hypertension. Persistence, adherence and compliance are interchangeable terms and have been used in the literature to describe a patient’s behaviour with their antihypertensive drugs and prescriptions. The methods used to determine persistence and adherence, as well as the inclusion and exclusion criteria, vary between persistence and adherence studies. The prevalence of persistence and adherence have varied between these studies, and were determined to be high in some studies and low in others. The initiation of a specific antihypertensive class has frequently been associated with an increase or decrease in adherence and persistence. The tolerability and efficacy of the initial antihypertensive class have been the most common methods of explaining this association. There are also many factors that suggest a relationship with adherence and persistence. Some factors in previous studies, such as age, were frequently associated with adherence and persistence. On the other hand, relationships with certain factors have varied between the studies. The associations of age, sex, alcohol use, smoking, baseline systolic blood pressure (SBP) and diastolic BP (DBP), the presence of comorbidities, an increase in the number of pills and the relationship between patients and physicians with adherence and persistence have been the most commonly investigated factors. Most studies have defined persistence in terms of a patient still taking medication after a period of time. A medication possession ratio (MPR) ≥ 80 has been used to define compliance. Either of these terminologies, or both, have been used to estimate adherence. In this study, I used the same definition for persistence to identify patients who have continued with their initial treatment, and used persistence and MPR to define patients who adhered to their initial treatment. The aim of this study was to estimate the prevalence of persistence and adherence in Scotland. Also, factors that could have had an effect on persistence and adherence were studied. The number of antihypertensive drugs taken by patients during the study and factors that led to an increase in patients being on a combination therapy were also evaluated. The prevalence of resistance and BP control were determined by taking the BP after the last drug had been taken by persistent patients during five follow-up studies. The relationship of factors such as age, sex, BMI, alcohol use, smoking, estimated glomerular filtration rate (eGFR), and albumin levels with BP reductions for each antihypertensive class were determined. Information Services Division (ISD) data, which includes all antihypertensive drugs, were collected from pharmacies in Scotland and linked to the Glasgow Blood Pressure Clinic (GBPC) database. This database also includes demographic characteristics, BP readings and clinical results for all patients attending the GBPC. The case notes for patients who attended the GBPC were reviewed and all new antihypertensive drugs that were prescribed between visits, BP before and after taking drugs, and any changes in the hypertensive drugs were recorded. A total of 4,232 hypertensive patients were included in the first study. The first study showed that angiotensin converting enzyme inhibitor (ACEI) and beta-blockers (BB) were the most prescribed antihypertensive classes between 2004 and 2013. Calcium channel blockers (CCB), thiazide diuretics and angiotensin receptor blockers (ARB) followed ACEI and BB as the most prescribed drugs during the same period. The prescription trend of the antihypertensive class has changed over the years with an increase in prescriptions for ACEI and ARB and a decrease in prescriptions for BB and diuretics. I observed a difference in antihypertensive class prescriptions by age, sex, SBP and BMI. For example, CCB, thiazide diuretics and alpha-blockers were more likely to be prescribed to older patients, while ACEI, ARB or BB were more commonly prescribed for younger patients. In a second study, 4,232 and 3,149 hypertensive patients were included to investigate the prevalence of persistence in the Scottish population in 1- and 5-year studies, respectively. The prevalence of persistence in the 1-year study was 72.9%, while it was only 62.8% in the 5-year study. Those patients taking ARB and ACEI showed high rates of persistence and those taking diuretics and alpha blockers had low rates of persistence. The association of persistence with clinical characteristics was also investigated. Younger patients were more likely to totally stop their treatment before restarting their treatment with other antihypertensive drugs. Furthermore, patients who had high SBP tended to be non-persistent. In a third study, 3,085 and 1,979 patients who persisted with their treatment were included. In the first part of the study, MPR was calculated, and patients with an MPR ≥ 80 were considered as adherent. Adherence rates were 29.9% and 23.4% in the 1- and 5-year studies, respectively. Patients who initiated the study with ACEI were more likely to adhere to their treatments. However, patients who initiated the study with thiazide diuretics were less likely to adhere to their treatments. Sex, age and BMI were different between the adherence and non-adherence groups. Age was an independent factor affecting adherence rates during both the 1- and 5-year studies with older patients being more likely to be adherent. In the second part of the study, pharmacy databases were checked with patients' case notes to compare antihypertensive drugs that were collected from the pharmacy with the antihypertensive prescription given during the patient’s clinical visit. While 78.6% of the antihypertensive drugs were collected between clinical visits, 21.4% were not collected. Patients who had more days to see the doctor in the subsequent visit were more likely to not collect their prescriptions. In a fourth study, 3,085 and 1,979 persistent patients were included to calculate the number of antihypertensive classes that were added to the initial drug during the 1-year and 5-year studies, respectively. Patients who continued with treatment as a monotherapy and who needed a combination therapy were investigated during the 1- and 5-year studies. In all, 55.8% used antihypertensive drugs as a monotherapy and 44.2% used them as a combination therapy during the 1-year study. While 28.2% of patients continued with treatment without the required additional therapy, 71.8% of the patients needed additional therapy. In all, 20.8% and 46.5% of patients required three different antihypertensive classes or more during the 1-year and 5-year studies, respectively. Patients who started with ACEI, ARB and BB were more likely to continue as monotherapy and less likely to need two more antihypertensive drugs compared with those who started with alpha-blockers, non-thiazide diuretics and CCB. Older ages, high BMI levels, high SBP and high alcohol intake were independent factors that led to an increase in the probability of patients taking combination therapies.

This complex practice as research project was designed to interrogate the potential of 'Traumaturgy', an emergent dramaturgical methodology, in addressing the many challenges of writing, staging, and performing, autobiographical trauma narratives and to understand the impact of this process on the psychic, and somatic memories, of the autobiographical performer. The methodology was designed to motivate complex reflections on personal and cultural traumata as critical provocations for the re-writing and performing of the memory-scripts associated with the autobiographical traumatic life events such as adoption, which are explored through the traumaturgical performance process. Rather than distracting the psyche from the autobiographical traumatic experience, the traumaturgy model functions by seeking to establish new internal cognitive networks: positive associations that might facilitate an empowering, liberating transition, initiated through the act of traumaturgically framed narrative performance. Models of trauma intervention locate narrative reconstructions of the traumatic experience as a central focus for the process of recovery (Eagle., 2000; Herman, 1992; Schwartz & Prout, 1991) etc, however, unlike expressive therapies (see Glading, 1991; Moreno, 1975) which exist within the relative safety of the applied theatre space, key to this methodology is the achievement of strategic closure, by returning the performance to the traditional theatre environment and inviting an audience to play the role of witness. This creative synthesis between trauma theory and dramaturgical responses to the staging, and performing of post-traumatic memory based materials, forms the axis of this methodological approach. The research-sharing event In Search of Duende, which represented the performative articulation of this thesis, culminated in the performance of the play Dancing For Franco, which sought to re-write, and re process the researcher’s autobiographical trauma-based memory scripts through its witnessed performance. The play takes the somatic language of flamenco intertwoven with the adoption narratives of the researcher, and individuals affected by the Francoist system of illegal baby theft which are collectively known as the Niños Robados (Spain’s Stolen Children), and the fictional narratives of created characters, to understand how the traumaturgy model might instigate transformational processes within the autobiographical performer.

Alzheimer’s disease is the most common of the degenerative brain diseases and is characterised by impairment of cognitive function. Patients with this disorder lose the ability to encode new memories. Eventually, both declarative and non-declarative memory is significantly impaired, resulting in the capacity for reasoning, abstraction and language becoming progressively reduced. Alzheimer’s disease and other dementias have devastating effects on families and caregivers, and is an increasing burden in an ageing society. It is estimated that 36 million people worldwide are living with dementia and this figure is expected to double every 20 years. The worldwide costs of dementia in 2010 were estimated to be $604 billion, an exorbitant figure that represents 1% of global GDP (World Alzheimer Report 2011). Alzheimer’s disease is the fourth leading cause of death in industrialised nations, preceded by cardiovascular disease, cancer and stroke. As yet there are currently no disease-modifying drugs approved to treat Alzheimer’s disease. The therapeutics that are available only temporarily alleviate symptoms of cognitive impairment, however, they do not halt the inevitable progression of the disease. As such, major scientific efforts are underway in order to develop drugs which can help stabilise the disease. The publication of the “Amyloid Hypothesis” by Dennis Selkoe in 1991 helped to focus research efforts towards a causative protein involved in the disease, the amyloid β protein (Aβ). Aggregation and deposition of the Aβ protein is fundamental in the aetiology of Alzheimer’s disease and its importance has been demonstrated by a number familial heterogeneous mutations in the amyloid precursor protein that promote increased Aβ deposition, resulting in early onset phenotypes. There are several other aspects involved in disease progression such as neuroinflammation and aberrant neuronal signalling, however, therapies targeting amyloid β aggregation have the potential to slow or even halt further neurodegeneration and anti-Aβ therapies are regarded as a logical approach to treating Alzheimer’s disease. Several endogenous pathways exist to prevent protein misfolding and subsequent aggregation following stressful cellular conditions. One pathway includes the amateur chaperones of the small heat-shock protein family, which have recently garnered interest due to their ability to inhibit the aggregation of amyloid-like proteins. In particular, Hsp20 was previously identified as having the ability to inhibit the aggregation of Aβ and could Abstract ii attenuate subsequent toxicity associated with Aβ peptides. Hsp20 was of particular interest to the Baillie group as it has well established cardio-protective functions, which are triggered by the phosphorylation of a serine residue (S16) at a consensus protein kinase A/G site. Hsp20 “activity” can therefore be readily modulated via inhibition of second messenger signal degradation by phosphodiesterases. The first part of this thesis investigated the interaction between Hsp20 and Aβ using Peptide Array technology. This technique allowed rapid characterisation of interacting domains and pinpointed key residues that mediated the protein-protein interaction. Using this approach, I demonstrated that the domain within Hsp20 that interacted with Aβ included the consensus PKA phosphorylation site (R-R-X-S). Upon introduction of a phospho-serine residue or a phospho-mimetic substitution, I was able to show that the binding of Aβ was enhanced. Reciprocal peptide array experiments highlighted that Hsp20 bound to a domain within Aβ, which is key to the aggregation of the Aβ peptide and is required to produce the higher order toxic Aβ species. The Peptide Array data was then verified using full-length recombinant proteins and several Hsp20 mutants were developed including a phospho-mimetic. The phospho-mimetic Hsp20 was shown to outperform the wild-type variant in several assays such as, in vitro pull-down assays, Aβ aggregation measured using nuclear magnetic resonance spectroscopy, and also a novel Aβ aggregation assay which can differentiate between two distinct aggregation pathways, namely fibrillisation and oligomerisation. These data demonstrated for the first time how the interaction between Hsp20 and Aβ may be modulated by cell signalling cascades. I then moved to investigate the cytotoxicity of Aβ in order to investigate whether increasing Hsp20 expression in neuronal-like cells would confer protection against Aβ-mediated toxicity. This was initially carried out using a standard MTT-based cell viability assay, before utilising a real-time cell monitoring device to develop a novel Aβ toxicity assay. In both assays, increasing Hsp20 expression was shown to be cytoprotective. The wild-type variant of Hsp20 was found to be more effective in cell-based assays due to increased levels of phosphorylated Hsp20. The real-time Aβ toxicity monitoring assay also gave me a platform for testing agents with potential neuroprotective properties. Given that increasing levels of phosphorylated Hsp20 could attenuate Aβ-mediated cytotoxicity, I logically was drawn to study ways that this event could be targeted therapeutically. Several drugs that target cAMP- and cGMP-dependent phosphodiesterases have been shown to be effective in alleviating symptoms of Alzheimer’s disease in rodent iii models have also been studied here in cellular systems. These included the “blockbuster” PDE5 inhibitor Viagra® (sildenafil), two novel compounds which selectively inhibit PDE9, which were developed by the pharmaceutical company Lundbeck specifically as Alzheimer’s treatments, and rolipram, a well established cognitive enhancer that was developed originally as an anti-depressant. All of these compounds were shown to “activate” endogenous Hsp20 to varying degrees in neuronal-like cells and the levels of Hsp20 activation was found to correlate with both the level of induced Hsp20/Aβ co-localisation, and subsequent attenuation of Aβ-mediated cytotoxicity. This suggests that this endogenous protection pathway can be targeted by currently available therapeutics in order to reduce the neurotoxic effects of Aβ. Finally, we wanted to develop novel agents of our own that could promote Hsp20 phosphorylation. To do this, in silico docking of all FDA approved drugs against the catalytic domain of PDE4 was undertaken in an attempt to find a novel compound with the potential to reposition as an Alzheimer’s treatment. Using this methodology we discovered an angiotensin converting enzyme inhibitor, moexipril to be a PDE4 inhibitor in the low micro molar range. Unfortunately, moexipril works as an ACE inhibitor in the low nano molar range making repositioning unviable. However, moexipril treatment was more effective than rolipram in reversing Aβ toxicity and I speculate that this may be due to the sub-family selective nature of its (moexipril) PDE4 inhibition. Furthermore, the lack of emetic side effects associated with moexipril makes this compound an ideal starting point for the development of isoform selective and/or non-emetic PDE4 inhibitor. In summary, these studies describe a novel endogenous mechanism for combating the toxic effects of the Aβ protein, which underpins the development and progression of Alzheimer’s disease. Given that the interaction between Hsp20 and Aβ can be manipulated via cAMP/cGMP signalling, the interaction could be targeted therapeutically. As there are currently no effective drugs on the market for stabilising Alzheimer’s disease, I believe that the data presented here opens up a potential new avenue that could lead to the development of a new class of AD drugs.

Soft tissue sarcomas (STS) comprise a heterogenenous group of greater than 50 malignancies of putative mesenchymal cell origin and as such they may arise in diverse tissue types in various anatomical locations throughout the whole body. Collectively they account for approximately 1% of all human malignancies yet have a spectrum of aggressive behaviours amongst their subtypes. They thus pose a particular challenge to manage and remain an under investigated group of cancers with no generally applicable new therapies in the past 40 years and an overall 5-year survival rate that remains stagnant at around 50%. From September 2000 to July 2006 I undertook a full time post-doctoral level research fellowship at the MD Anderson Cancer Center, Houston, Texas, USA in the department of Surgical Oncology to investigate the biology of soft tissue sarcoma and test novel anti- sarcoma adenovirus-based therapy in the preclinical nude rat model of isolated limb perfusion against human sarcoma xenografts. This work, in collaboration with colleagues as indicated herein, led to a number of publications in the scientific literature furthering our understanding of the malignant phenotype of sarcoma and reported preclinical studies with wild-type p53, in a replication deficient adenovirus vector, and oncolytic adenoviruses administered by isolated limb perfusion. Additional collaborative and pioneering preclinical studies reported the molecular imaging of sarcoma response to systemically delivered therapeutic phage RGD-4c AAVP. Doxorubicin chemotherapy is the single most active broadly applicable anti-sarcoma chemotherapeutic yet only has an approximate 30% overall response rate with additional breakthrough tumour progression and recurrence after initial chemo-responsiveness further problematic features in STS management. Doxorubicin is a substrate for the multi- drug resistance (mdr) gene product p-glycoprotein drug efflux pump and exerts its main mode of action by induction of DNA double-strand breaks during the S-phase of the cell cycle. Two papers in my thesis characterise different aspects of chemoresistance in sarcoma. The first shows that wild-type p53 suppresses Protein Kinase Calpha (PKCα) phosphorylation (and activation) of p-glycoprotein by transcriptional repression of PKCα through a Sp-1 transcription factor binding site in its -244/-234 promoter region. The second paper demonstrates that Rad51 (a central mediator of homologous recombination repair of double strand breaks) has elevated levels in sarcoma and particularly in the S- G2 phase of the cell cycle. Suppression of Rad51 with small interfering RNA in sarcoma cell culture led to doxorubicin chemosensitisation. Reintroduction of wild-type p53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression via transcriptional repression of the Rad51 promoter through increased AP-2 binding. In light of poor response rates to chemotherapy, escape from local control portends a poor prognosis for patients with sarcoma. Two papers in my thesis characterise aspects of sarcoma angiogenesis, invasion and metastasis. Human sarcoma samples were found to have high levels of matrix metalloproteinase-9 (MMP-9) with expression levels that correlated with p53 mutational status. MMP-9 is known to degrade extracellular collagen, contribute to the control of the angiogenic switch necessary in primary tumour progression and facilitate invasion and metastasis. Reconstitution of wild-type p53 function led to decreased levels of MMP-9 protein and mRNA as well as zymography-assessed MMP-9 proteolytic activity and decreased tumour cell invasiveness. Reintroduction of wild-type p53 into human sarcoma xenografts in-vivo decreased tumour growth and MMP-9 protein expression. Wild-type p53 was found to suppress mmp-9 transcription via decreased binding of NF-κB to its -607/-595 mmp-9 promoter element. Studies on the role of the VEGF165 in sarcoma found that sarcoma cells stably transfected with VEGF165 formed more aggressive xenografted tumours with increased vascularity, growth rate, metastasis, and resistance to chemotherapy. Use of the anti-VEGFR2 antibody DC101 enhanced doxorubicin sensitivity at sub-conventional dosing, inhibited tumour growth, decreased development of metastases, and reduced tumour micro-vessel density while increasing the vessel maturation index. These effects were explained primarily through effects on endothelial cells (e.c.s), rather than the tumour cells per se, where DC101 induced e.c. sensitivity to doxorubicin and suppressed e.c. production of MMPs. The p53 tumour suppressor pathway is the most frequently mutated pathway in sarcoma. Recapitulation of wild-type p53 function in sarcoma exerts a number of anti-cancer outcomes such as growth arrest, resensitisation to chemotherapy, suppression of invasion, and attenuation of angiogenesis. Using a modified nude rat-human sarcoma xenograft model for isolated limb perfusion (ILP) delivery of wild-type p53 in a replication deficient adenovirus vector I showed that functionally competent wild-type p53 could be delivered to and detected in human leiomyosarcoma xenografts confirming preclinical feasibility - although not efficacious due to low transgene expression. Viral fibre modification to express the RGD tripeptide motif led to greater viral uptake by sarcoma cells in vitro (transductional targeting) and changing the transgene promoter to a response element active in cells with active telomerase expression restricted the transgene expression to the tumour intracellular environment (transcriptional targeting). Delivery of the fibre-modified, selectively replication proficient oncolytic adenovirus Ad.hTC.GFP/ E1a.RGD by ILP demonstrated a more robust, and tumour-restricted, transgene expression with evidence of anti-sarcoma effect confirmed microscopically. Collaborative studies using the fibre modified phage RGD-4C AAVP confirmed that systemic delivery specifically, efficiently, and repeatedly targets human sarcoma xenografts, binds to αv integrins in tumours, and demonstrates a durable, though heterogeneous, transgene expression of 1-4 weeks. Incorporation of the Herpes Simplex Virus thymidine kinase (HSVtk) transgene into RGD-4C AAVP permitted CT-PET spatial and temporal molecular imaging in vivo of transgene expression and allowed quantification of tumour metabolic activity both before and after interval administration of a systemic cytotoxic with predictable and measurable response to treatment before becoming apparent clinically. These papers further the medical and scientific community’s understanding of the biology of soft tissue sarcoma and report preclinical studies with novel and promising anti- sarcoma therapeutics.