Photodynamic therapy (PDT) is an experimental cancer treatment that is based on the systemic administration of tumor-localizing photosensitizers and subsequent excitation with visible light to produce tumor destruction. This destruction is primarily mediated by energy transfer of excited photosensitizer to molecular oxygen, producing cytotoxic singlet oxygen. Tumor treatment by PDT is accompanied by changes to tumor and normal tissue microvasculature. These changes include vasoconstriction, platelet aggregation, and lead to vascular stasis and decreased tumor oxygenation. Animal studies have shown that vascular stasis and ensuing hypoxia are critical to tumor destruction. The mechanisms producing these changes have not extensively investigated although they are likely central to an understanding of how PDT induces tumor destruction. A complete understanding of these processes is necessary to develop new treatment strategies and increase the efficacy of clinical treatment. We hypothesize that PDT results in the release of singlet oxygen from either blood components (platelets), perivascular tissues, or endothelial cells. These molecules interact with the lipid components of membranes, lead to the liberation of arachidonic acid and its metabolites, and enhance the dominance of proaggregatory constrictor metabolites (thromboxane) over antiaggregatory dilator metabolites (prostacyclin). This condition will lead to vasoconstriction, platelet aggregation and hemostasis. Our experimental plan is to first characterize the intravascular release of thromboxane and prostacyclin following PDT using three different photosensitizers, over a range of drug and light doses. Thromboxane and prostacyclin levels in serum will be assessed by radioimmunoassay. These results will be compared to measurements of the relative effectiveness of these different photosensitizers to produce vascular damage and tumor destruction. Secondly, we will employ different classes of drugs which inhibit the release of eicosanoids at specific stages in their metabolic pathway. Studies will emphasize the use of these inhibitory agents to clarify the mechanistic pathways and identify the cellular targets for PDT- induced vascular damage. WE will determine how these agents influence PDT- induced release of eicosanoids, and relate this to vascular damage, vascular leakage, tissue edema, tumor response, skin damage and cutaneous hypersensitivity.
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