This is a five year proposal to continue studies on the mechanism(s) and efficacy (human) of photodynamic therapy (PDT) of cancer. This is a combined basic and applied approach involving basic scientists and clinicians. Studies are proposed at three levels: (1) subcellular/cellular, (2) tissue/animal, (3) human clinical. HpD (DHE/Photorin II) will be investigated and compared to new photosensitizers that will be synthesized by a collaborating chemist. The subcellular and cellular studies will involve studies on (a) subcellular binding, (b) kinetics of sensitizer uptake and excretion, (c) cellular phototoxicity, (d) detection and measurement of singlet oxygen. The tissue and animal model studies will involve (a) examination of three rodent animal models (EMT-6, RIF, and rat colon adenocarcinoma), (b) a vascular chicken comb model, (c) and angiogenic-induce ocular vascular model. The mechanism of PDT will be examined using techniques of histology, electron microscopy, spectroscopy, and cell culture. The human clinical studies will involve correlation of tumor fluorescence with therapeutic response in recurrent breast cancer, and the development of a topical application of photosensitizer for the treatment of early stage neoplasia in the gynecological tract.