Photodynamic therapy (PDT) of cancer and of various other conditions continues to gain clinical acceptance. The approvals of three photosensitizing drugs, Photofrin, Visudyne and Levulan, in the United States and the ongoing clinical evaluation of several promising new agents throughout the world provide the context for ongoing laboratory studies that are designed to understand further and to optimize this therapy. During the past several years, the field has gained a deeper appreciation of the complex and dynamic interactions among the photosensitizing drug, light, and oxygen that together define the dosimetry of PDT. Research in this laboratory has been directed at defining quantitatively the consequences of therapy-induced, photochemical oxygen consumption for therapeutic outcome. A critically important aspect of this effort is to define more precisely and in a manner that can be translated into clinically relevant measurements the relationship between the photodegradation of the sensitizing drug, the PDT-induced consumption of oxygen, the detailed deposition of photodynamic dose and the biological response. This in turn requires improved methods for performing and analyzing results from fluorescence spectroscopy in tumors and for the noninvasive assessment of tumor oxygenation. Toward these general ends, the application poses the following three specific aims: (1) to expand the experimental investigation and theoretical analysis of the oxygen problem in PDT; (2) to establish the ability of sensitizer fluorescence spectroscopy to report biological response of tumors in vivo and to investigate the feasibility of simultaneous spectroscopic assessment of blood oxygen, NADH and sensitizer bleaching/photoproduct kinetics from spatially resolved measurements of fluorescence; and (3) to determine the PDT threshold dose for induction of specific genes and the specific severity and duration of PDT-induced hypoxia required to induce the expression of hypoxia-inducible factor-10c. The experimental methods that will be used to accomplish these aims include the use of O2-sensitive microelectrodes, laser scanning optical sectioning fluorescence microscopy and microspectrofluorimetry, fluorescence spectroscopy in vivo and diffuse reflectance absorption spectroscopy. ? ?
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