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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA051771-03
Application #
3196433
Study Section
Radiation Study Section (RAD)
Project Start
1990-05-09
Project End
1994-01-31
Budget Start
1992-05-01
Budget End
1994-01-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
Fingar, V H; Taber, S W; Haydon, P S et al. (2000) Vascular damage after photodynamic therapy of solid tumors: a view and comparison of effect in pre-clinical and clinical models at the University of Louisville. In Vivo 14:93-100
Fingar, V H; Kik, P K; Haydon, P S et al. (1999) Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD). Br J Cancer 79:1702-8
ten Tije, A J; Wieman, T J; Taber, S W et al. (1999) Analysis of pulmonary microvasculature changes after photodynamic therapy delivered to distant sites. Photochem Photobiol 69:494-9
Fingar, V H; Wieman, T J; Haydon, P S (1997) The effects of thrombocytopenia on vessel stasis and macromolecular leakage after photodynamic therapy using photofrin. Photochem Photobiol 66:513-7
Fingar, V H; Taber, S W; Buschemeyer, W C et al. (1997) Constitutive and stimulated expression of ICAM-1 protein on pulmonary endothelial cells in vivo. Microvasc Res 54:135-44
Fingar, V H; Wieman, T J; McMahon, K S et al. (1997) Photodynamic therapy using a protoporphyrinogen oxidase inhibitor. Cancer Res 57:4551-6
Fingar, V H (1996) Vascular effects of photodynamic therapy. J Clin Laser Med Surg 14:323-8
McMahon, K S; Wieman, T J; Moore, P H et al. (1994) Effects of photodynamic therapy using mono-L-aspartyl chlorin e6 on vessel constriction, vessel leakage, and tumor response. Cancer Res 54:5374-9
Fingar, V H; Taber, S W; Wieman, T J (1994) A new model for the study of pulmonary microcirculation: determination of pulmonary edema in rats. J Surg Res 57:385-93
Fingar, V H; Siegel, K A; Wieman, T J et al. (1993) The effects of thromboxane inhibitors on the microvascular and tumor response to photodynamic therapy. Photochem Photobiol 58:393-9

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