As described in other sections of this program project application, there is a critical need to develop new photosensitizers with improved therapeutic efficacy and low phototoxicity. Since the phthalocyanines have shown promise in this regard the purpose of the studies outlined in this proposal is to develop new knowledge regarding their potential usefulness in photodynamic therapy of cancer. RIF-1 transplanted tumors and chemically induced murine skin neoplasms have been selected as tumor models to assess photodynamic therapy responses. This choice is made because each model has some advantages and will provide complimentary data in transplanted tumors and in tumors developed in their own tissue matrix. Virtually no studies have been conducted to define the photodynamic therapy and photosensitizing and/or phototoxic effects of phthalocyanines in the skin. In aims 1 and 2, candidate phthalocyanine will be used to define their pharmacodynamic and phototoxic effects in C3H/HeJ mice implanted with RIF-1 tumors and in C3Hf/HeN mice bearing chemically-induced benign papillomas and squamous cell carcinomas in assay procedures operational in this laboratory. Skin photosensitivity response to the phthalocyanines will also be studied. In vivo mechanisms of photodynamic therapy with phthalocyanines will also be studied. In aim 3, promising phthalocyanines will be studied for dark systemic toxicity and changes in immunological responses in animals treated with phthalocyanine-based photodynamic therapy. Based on these studies we will select the most promising phthalocyanine for detailed mechanistic studies. In aim 4, the mechanism of phthalocyanine photosensitization will be studied in normal and malignant human epidermal keratinocytes to complement and further expand the data obtained from the animal studies. The role of reactive oxygen species in this process including superoxide anions, hydrogen peroxide, hydroxyl radical and singlet oxygen will be explored using quenchers and spin traps combined with electron spin resonance spectroscopy. The role of lipid peroxidation as a mechanism of phthalocyanine photosensitization will also be studied. Where appropriate, the photosensitizing effects of phthalocyanines will be compared with those of Photofrin II as a positive control in an effort to determine the superiority of one or another of these classes of photosensitizer for photodynamic therapy. The purpose of these studies is to develop a broader base of knowledge regarding the usefulness of phthalocyanines for the photodynamic therapy of cancer.