OVERALL DESCRIPTION (Applicant's Description) The proposed program project is a continuation and expansion of a pre-clinical program in photo-dynamic therapy (PDT) that was first funded in 1990. The current goals are to elucidate mechanisms of PDT response in molecular, cellular, and normal and tumor tissue systems; to improve understanding of the structure-activity relationships of phthalocyanines related to our lead photosensitizer Pc 4; and to initiate clinical development of Pc 4. There are four projects. In Project 1, a series of phthalocyanines will be synthesized with structures designed to aid understanding of the action of Pc 4. The compounds will be characterized structurally, and their photophysics and photochemistry will be examined. In Project 2, the mechanisms of cellular responses to PDT will be studied, with an emphasis on localization in mitochondria, the induction of apoptosis in cells and tumors, and the activation of stress pathways. In Project 4, a phase I (+/- II) trial of PDT with Pc 4 will be undertaken for cutaneous basal and squamous cell carcinoma and tumors metastatic to the skin. A linked translational study will follow Pc 4 pharmacokinetics in plasma and tumor and the incidence of apoptosis and an associated biochemical marker. The projects will be aided by three core facilities: Core A for light sources and confocal microscopy; Core B for administration; and Core D for photosensitizer evaluation. Important collaborative efforts of the projects and cores include evaluation of structure-activity relationships of sets of phthalocyanines, and determination of the roles of apoptosis and expression of adhesion molecules in the response of tumors to Pc 4-PDT. The combined program should further develop a promising photosensitizer for clinical PDT, provide new understanding of PDT mechanisms, and clarify structural requirements of an efficacious phthalocyanine photosensitizer.