This thesis is an investigation of the use of thrombospondin-1 mimetic peptides for the treatment of epithelial ovarian cancer. The current standard of care for women diagnosed with ovarian cancer is surgical de-bulking followed by chemotherapeutics. Initially, this treatment regimen results in a reduction in the primary tumor, unfortunately chemoresistance and disease recurrence are problematic. Recent data has suggested a potential role for anti-angiogenic therapy for the treatment of various cancers. Therefore, the purpose of this study was to investigate the use of mimetics consisting of the anti-angiogenic domain of thrombospondin-1 (TSP-1) for the treatment of epithelial ovarian cancer (EOC) using a mouse model of the disease. The peptides were applied at various stages of tumor progression and a significant reduction in tumor size following treatment was observed. We found that not only were the peptides capable of slowing down tumor progression but they also played a role in reducing the size of established tumors. Treatment with TSP-1 mimetics also resulted in a significant reduction in secondary lesions and ascites fluid in the peritoneal cavity of animals. A significant increase in disease-free survival was also identified following long-term treatment with the peptide. Various histological studies revealed that the anti-angiogenic peptide was in fact inducing apoptosis of the endothelial cells and also re-organizing the vasculature. To determine whether this resulted in increased blood vessel profusion we applied standard chemotherapeutics in combination with TSP-1 mimetics. Experiments with radiolabelled and fluorescent chemotherapeutics demonstrated that pre-treating with TSP-1 mimetics allowed the vasculature to become normalized and resulted in an increased uptake of chemotherapeutics. Lastly, we investigated the mechanism of action of anti-angiogenic peptides. Most of the anti-tumor effects appeared to be due to the apoptotic effects of TSP-1 mimetics on the vasculature. A direct apoptotic effect on epithelial cells also was observed; however, it is uncertain how much of a role this plays. In conclusion, this study was important for identifying TSP-1 mimetic peptides as a potential therapeutic treatment for women suffering from EOC.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OGU.10214/3571 |
| Date | 07 May 2012 |
| Creators | Campbell, Nicole |
| Contributors | Petrik, Jim |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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