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The primary aim of this study is to assess the predictive value of six molecular markers in determining PRCa risk in patients with BPH. These molecular markers are: (A)- Two polymorphic repeats, (CAG)_n and (GGN)_n, in the androgen receptor (<i>AR</i>) gene; (B)- A single nucleotide polymorphism (SNP) in the (-290 A to G) 5' regulatory region of the <i>CYP3A4 </i>gene; (C)- Two SNPs (<i>Taq</i>I and <i>Fok</i>I) in vitamin D receptor (<i>VDR</i>) gene; (D)- A SNP (Val655Ile) in the transmembrane domain coding region of <i>HER2</i> gene. The study evaluated 28 patients who presented with PRCa at least 3 years and up to 15 years after the diagnosis of BPH and 56 matched patients with BPH who did not progress to PRCa over a comparable period. The results of this study showed that <i>CYP3A4</i> variant genotype identified men with BPH who are at increased risk of developing PRCa (odds ratio 5.2, 95% CI = 1.8-14.3). Similar finding was also seen for <i>VDR Taq</i>I SNP, where TT genotype was associated with a significant 5 fold increase in the risk of developing PRCa in patients previously diagnosed with BPH. Tentative evidence of association between risk of developing PRCa and the variant genotype of <i>HER2 </i>and <i>VDR Fok</i>I SNPs was also demonstrated, although the results were not statistically significant. The odds ratio of developing PRCa was 1.88, and 2.33 in BPH patients having <i>HER</i>2 Ile/Ile genotype and <i>VDR Fok</i>I FF genotype respectively. This study also showed no evidence for association between the size of <i>AR </i>CAG and GGN repeats and the risk of the development of PRCa in patients with BPH. However, data of this study suggest that BPH patients with <i>AR </i>CAG instability have a 12 fold increase risk in development PRCa. These results provide a potential tool to assist prediction strategies for this important disease.

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University of Macau / Faculty of Health Sciences

Prostate cancer (PCa) is the second most common cause of cancer-related deaths in men in the Western world. Advanced PCa is initially managed by anti-androgen therapy however, resistance frequently develops resulting in progressive metastatic disease. The current standard of care for hormone-insensitive PCa includes the cytotoxic drugs docetaxel and mitoxantrone although resistance rapidly develops to all available therapies. We demonstrated that the replication-selective oncolytic adenoviral mutant AdΔΔ enhanced drug-induced cell killing in several preclinical cancer models. AdΔΔ is deleted in the viral E1ACR2 and E1B19K, to prevent pRb-binding and enhance drug-mediated apoptotic cell killing, respectively. In drug-insensitive PCa tumour-xenografts, in vivo administration of AdΔΔ greatly enhanced drug-mediated tumour regression. The aim of my thesis project was to investigate the role of apoptosis and pro-survival pathways, including drug-induced autophagy, in AdΔΔ-mediated drug-sensitisation. I have demonstrated that autophagy was activated in a dose-dependent manner in response to mitoxantrone in the human PCa cell lines PC3, PC3M and 22Rv1. Low doses of mitoxantrone (< EC50-values) caused initiation of autophagy, determined as increased conversion of LC3I to LC3II and increased number of acidic vesicles, indicating autophagosome formation. At higher doses degradation of p62 was also observed, suggesting autophagosome fusion with the lysosome. AdΔΔ attenuated the drug-induced activation of autophagy by restoring basal LC3II/I ratios, and increasing apoptosis, determined as increased PARP-cleavage and mitochondrial depolarization. The autophagyinducer rapamycin prevented AdΔΔ-mediated sensitization in PC3 cells increasing mitoxantrone EC50-values 3-fold and attenuating apoptosis induction. In contrast, the autophagy-inhibitor chloroquine further sensitized PC3 and 22Rv1 cells to the combinationtreatment, decreasing mitoxantrone EC50-values by 40% and increasing apoptotic cell death. Atg7 is a key-factor in the autophagy pathway and siRNA-mediated knockdown prevented increases in LC3II/I ratios. In siAtg7-transfected PC3 cells mitochondrial depolarization was further promoted in combination-treated cells, similar to the results with chloroquine. The cellular Bcl-2-protein has important roles as a mediator of both anti-apoptotic and antiautophagic functions. In cells transfected with siBcl-2 the LC3II/I ratios increased and AdΔΔ- mediated sensitization to mitoxantrone was prevented, indicating initiation of autophagy. In addition, mitoxantrone-induced degradation of Bcl-2 was attenuated by AdΔΔ infection, suggesting stabilization of the protein. The mechanisms for the AdΔΔ-mediated increases in cell killing were also demonstrated in 3-dimensional co-culture models of PC3 or 22Rv1 in combination with prostate stromal cells and extracellular matrix proteins using confocal microscopy. These data demonstrate that AdΔΔ attenuates drug-induced cell survival/rescue and promotes elimination of cancer cells through apoptosis and viral lysis, and that Bcl-2 was essential for the sensitisation.

Thesis (M.S.)--University of Delaware, 2007. / Principal faculty advisors: Robert A. Sikes and Randall Duncan, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (M. Med. Sc.)--University of Hong Kong, 2007.

Thesis (M.S.) -- Worcester Polytechnic Institute. / Keywords: Nutraceuticals; Prostate cancer; 5-Androstenediol. Includes bibliographical references (p.71-76).

Thesis (M.Med.Sc.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 89-94)

Thesis (Ph. D.)--Oregon State University, 2009. / Printout. Includes bibliographical references (leaves 109-123). Also available on the World Wide Web.