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Resistance to chemotherapy has been reported in various malignancies and constitutes a major challenge in cancer care. Over the years, several pathways have been suggested in the literature, but the mechanisms behind resistance to treatment remain unclear. Testicular germ cell tumours (TGCTs), the most common malignancy in young men, are known for their extreme sensitivity to cisplatin-based chemotherapy and their excellent clinical outcome, making them an ideal tumour model for the investigation of cisplatin-induced sensitivity and resistance.

In normal breast and ductal carcinoma ill situ, myoepithelial cells surround the luminal cell population and form an interface with the basement membrane. In invasive breast cancers, the myoepithelial layer is lost. The aim of this project was to analyse the effect of normal breast myoepithelial cells on breast cancer cells and to investigate potential mechanisms of their modulatory activity. Using isolated primary myoepithelial cells and a myoepithelial cell line, 2-D and 3-D co-culture systems were used to analyse the effects of myoepithelial populations on breast tumour cell growth. cDNA microarray analysis identified pathways modulated by the myoepithelial populations, confirmed by real-time RT -PCR and Western blot analysis, and RNAi knockdown of target genes established a role for specific molecules in the myoepithelial modulation of tumour behaviour. Co-culture with the myoepithelial populations resulted in significant decrease in tumour cell proliferation and significant enhancement in apoptosis, in T47-D and MDA-MB- 468 breast cancer cell lines, in both 2-D and 3-D systems. Co-cultures with a normal luminal epithelial cell line showed no significant effect on tumour cell function, indicating that this growth suppressor effect was myoepithelial-specific. cDNA microarray analysis identified a number of potential tumour-suppressor genes that were up-regulated in T47-D cells grown in tlie presence of primary myoepithelial cells. These included the calcium-binding proteins SlOOA9 and SlOOA8, which showed an approximately 30-fold and 14-fold increase, confirmed by real-time RT -PCR and Western blotting.

d1922-947 is a type 5 adenovirus deleted in a portion of its genome, EIA CR2, which releases E2F by binding retinoblastoma protein (PRb). Transactivation of E2Fresponsive genes stimulates S phase entry and viral DNA is preferentially replicated. Since over 90% of human cancers have pRb pathway abnormalities, d1922-947 replicates selectively in malignant cells. Co-immunoprecipitation in IGROVI human ovarian cancer cells and cytotoxicity in hTERT and SV 40 immortalised ovarian epithelial cells confirmed the proposed mechanism of d1922-947 activity. In IGROVI cells, d1922~947 induced S phase and viral protein expression more rapidly, and replicated more efficiently, than Ad5 WT. Cytotoxicity of d1922-947 exceeded Ad5 WT and the EIB 55K deleted adenovirus, . d11520. In female nude mice bearing intraperitoneal (IP) IGROVI xenografts, d1922- 947 increased survival above control (p<0.001), particularly when delivered in icodextrin. Hepatotoxicity, which was less severe than Ad5 WT, was seen in some nude mice treated with d1922-947 and in immunocompetent .C57B1I6 mice bearing CMT64 murine non.,.small cell lung cancer cells IP. Transformed murine ovarian epithelial cells (IDS) did not' suppoli production of late adenovirai proteins, despite efficient DNA replication, transcription and nuclear export of late viral RNAs. This could explain the .inability of IP viruses to improve survival in C57B1I6 mice bearing ID8 cells IP . . Ovarian cancer disseminates diffusely across peritoneal surfaces, so quantifying ill VIVO eIhcacy IS pro51emauc. In IllICe oeanng ll' xenograIts 01 FIreny Iucnerase expressing IGROVI cells (IGROVI-Luc), light output increased over time, whereas IP d1922-947 held bioluminescence at baseline for over two months. A Renilla relliformis luciferase expressing EIA CR2 deleted adenovirus, dlCR2 Ren, was created, which had comparable ,anti-tumour efficacy to dI922-.947. Light emission by dlCR2 Ren correlated with EIA expression and, after a single IP injection in murine models of ovarian cancer, light emission and therefore viral' persistence was demonstrated for 2 weeks.

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