The long-term objective of our research is to enhance the efficacy of Photodynamic Therapy (PDT) for treating cancer. In PDT, properties of photosensitizer localization in tumor tissue and photochemical generation of reactive oxygen species are combined with precise delivery of laser-generated light to produce a procedure offering local tumoricidal activity. PDT induced cytotoxicity can involve both direct tumor cell killing and vascular damage within the treated tumors. The rationale for our application builds upon recently obtained preliminary data. We have discovered that PDT serves as a molecular activator leading to the increased expression of angiogenic factors in exposed tumors. PDT induces expression of the hypoxia inducible factor-i alpha (HIF-la) transcription factor and also increases protein levels of the HIF- 1a target gene, vascular endothelial growth factor (VEGF), within tumor tissue. Additional proangiogenic genes may also be up-regulated following PDT. We hypothesize that combining PDT with antiangiogenic therapy will significantly improve the therapeutic responsiveness of solid tumors to PDT.
Two specific aims will address our hypothesis; (1) to identify the specific pro-angiogenic genes, which are activated by PDT, and to determine the particular PDT treatment parameters/mechanisms, which induce expression of pro-angiogenic genes; and (2) to determine the therapeutic effectiveness of PDT combined with antiangiogenic therapy. Antiangiogenic agents, which target growth factor function, integrins or MMPs, will be examined. Human and mouse tumor cells and microvascular endothelial cells will be used in molecular, biochemical and in-vivo experiments to address our specific aims. Completion of this project will provide both a mechanistic foundation regarding PDT induced expression of angiogenic molecules and a thorough preclinical evaluation of the therapeutic significance of combining antiangiogenic procedures with PDT for the treatment of cancer.
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