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Androgen deprivation therapy (ADT) is a cornerstone treatment option for men with metastatic or locally advanced prostate cancer, however, treatment with ADT has been associated with increased incidence of adverse cardiovascular events. Strategies to investigate and monitor cardiovascular risk, as well as to reduce such treatment-related morbidity are urgently required in this population. Study 1 of this thesis investigated the differences in endothelial function between men with advanced prostate cancer treated with ADT and matched controls using a case-control design. Flow-mediated dilatation (FMD) and glyceryl-trinitrate (GTN)-mediated dilatation of the brachial artery were assessed in 20 men (69 +/- 7 years) with prostate cancer treated with ADT for a median of 22 months (range 6-133 months) and compared against 20 controls (69 +/- 5 years) matched for age, history of cardiovascular disease and physical activity levels. FMD was reduced in men on ADT compared to controls (P 0.05). These findings provide novel data to suggest endothelial function is impaired in men with prostate cancer treated with ADT, which is in agreement with evidence of increased cardiovascular risk in this population. Study 2 investigated the effects of a 12-week lifestyle intervention including supervised exercise training and dietary advice on markers of cardiovascular health and general well-being in men treated with ADT for prostate cancer. Fifty men treated with ADT for &ge;6 months were randomly allocated to receive the intervention or usual care. Assessments of vascular function, blood pressure, body composition, exercise tolerance and psychological well-being were undertaken prior to randomisation (baseline) and after completion of the intervention (end-point), with a follow-up assessment completed a further 12 weeks after end-point assessments. Statistically significant differences between groups were observed for changes in skeletal muscle mass, body fat percentage, exercise tolerance, quality of life and fatigue (P < 0.05). In addition, clinically meaningful effect sizes were observed for the difference between groups for the change between baseline and end-point in FMD and diastolic blood pressure (d >0.51), with post-hoc analysis demonstrating a statistically significant change in FMD in men in the intervention group (P = 0.038). These findings support evidence that diet and exercise can improve general well-being of patients treated with ADT, and provide novel data on the effects of such an intervention on cardiovascular health.

Prostate cancer is a very important health problem in the UK and worldwide. Available treatments such as radiotherapy, surgery and androgen ablation have failed to significantly increase the life expectancy of prostate cancer patients. Therefore researching new treatments is paramount. A promising approach for prostate cancer is suicide gene therapy. In this work, the use of the NTR/CB1954 enzyme/prodrug system delivered by a baculovirus vector was investigated for its application in prostate cancer cell lines and prostate primary epithelial cultures. The results suggest that the NTR/CB1954 system is highly efficient in causing cell death in prostate cell lines and prostate primary epithelial cultures. The use of a baculovirus vector to deliver the NTR gene resulted in increased transduction of prostate cancer cell lines in comparison to non-malignant prostate and non-prostate cell lines. To target NTR expression to prostate cells the regulation of the hTGP promoter was dissected. hTGP expression was confirmed to be highly prostate specific and mainly regulated by retinoic acid, androgens, retinoic acid receptor gamma and the androgen receptor. This work presents the first evidence of an interaction between these nuclear receptors and challenges the current model for prostate specific expression. Finally a baculovirus encoding the NTR gene under the control of the hTGP promoter was tested in prostate cancer cell lines resulting in moderate cell death. These findings are very encouraging but in order to use the hTGP promoter for gene therapy there needs to be further manipulation of the sequence to optimise its potency while maintaining its prostate specificity. The use of NTR and baculovirus coupled to the targeting controlled provided by the hTGP promoter could develop into a potent and specific approach to treat prostate cancer.

INTRODUCTION: Men's health generally and testicular cancer in particular are neglected areas of research. This particular malignancy is the most common among young men in the western world (Champion, 1996), and its prevalence is on the increase, however, so too are cure rates. As a consequence there are an increasing number of young male survivors. Impact on sexual function of survivors is well documented in the literature, yet little is mentioned about the impact on the sexuality and masculinity of the young man following treatment. The objective of the research therefore was to explore the impact on survivor's self-perceptions,in particular focusing on the areas of sexuality, masculinity and body image. METHOD: The research followed a cross-sectional design, comparing men at four different stages post-illness. Repertory grid technique was utilised for data collection purposes, which combined qualitative and quantitative methods. Semi-structured interviews (n = 10) were analysed using content analysis, which formed the basis of a generic repertory grid. Quantitative data from subsequent grid completion (n = 37)were analysed using a beta version of SPSS to carry out 3-way 3-mode multidimensional unfolding. RESULTS: The results suggest that men's self-perceptions change as a consequence of testicular cancer, and that sexuality, masculinity and body image play a part in these changes for some, but not all men. The constructs rated in this study all contribute to the differences in patterns across groups. Results suggest the occurrence of an adjustment process, showing current perceptions of the self as more aligned with retrospective pre-illness perceptions by 24 months post-illness. The majority of men judged repertory grid technique to be a satisfactory means of evaluating self-perceptions relating to the illness experience. DISCUSSION: The results of the study have implications for the level of professional support received by men with testicular cancer, both generally and with specific reference to issues of sexuality, masculinity and body image. However the innovative style of this research and the absence of pre-existing evidence in support of the findings, mean that further research will be required to gain a thorough understanding of the psychological implications of surviving testicular cancer with regards to these issues. Specific recommendations are made for further research

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