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Metronomic chemotherapy is a unique low dose chemotherapeutic approach that affects pro-angiogenic and immunosuppressive characteristics of cancer. Induction of apoptosis in activated vascular endothelial cells and regulatory T cells in cancer patients indirectly lead to anti-cancer effects. Oral low dose administration of cytotoxic drugs reduces the adverse events commonly encountered with the conventional chemotherapy; however, the continuous chronic scheduling carries different toxicity risks. Active patient selection and individualized protocol modification of metronomic protocols would hence be ideal to avoid detrimental toxicity risks and maximize clinical application. This thesis investigated the urokinase plasminogen activator (uPA) system as a possible biomarker of metronomic chemotherapy. The first set of studies examined the efficacy and toxicity of metronomic cyclophosphamide in three cohorts of dogs with cancer. Addition of commonly used maintenance metronomic protocols did not improve the outcome of dogs with hemangiosarcoma or osteosarcoma, and cumulative cyclophosphamide dose was found to be a risk factor for sterile hemorrhagic cystitis development. Urokinase plasminogen activator and its receptor uPAR contribute to local invasion and systemic metastasis and are often activated in malignant cancers. High expression of uPA and uPAR are associated with poor prognosis across diverse human cancer types. In the second section, tissue and circulating levels of uPA and uPAR were assessed by tissue microarray immunohistochemistry and serum enzyme-linked immunosorbent assay (ELISA) in dogs with osteosarcoma, revealing that the majority of canine osteosarcoma tissues expressed both uPA and uPAR, with accompanying increased serum uPA level in canine osteosarcoma patients. High serum uPA level and activity were both significantly associated with poor patient outcome. Finally, the uPA system was analyzed in a pilot clinical trial of 7 dogs with soft tissue sarcoma in vivo and cultured cancer and endothelial cells in vitro. There was a reduction in tissue and serum uPA/uPAR levels in correspondence with tumour volumetric change in one dog with a partial response to metronomic cyclophosphamide treatment. In vitro treatment did not show uPA or uPAR expression changes in any of the 7 cell lines tested. Overall, this thesis presents the feasibility and potential prospective application of uPA as a prognostic and treatment biomarker in dogs undergoing metronomic chemotherapy. Heterogeneous tumour responses and characteristics were highlighted, and this research may serve as a foundation for further uPA-related research to better assess its accuracy and limitations with regard to clinical decision making about the use of metronomic chemotherapy in dogs with osteosarcoma. Ontario Veterinary College Pet Trust 2022-08-16 |
