The use of photosensitizing chemicals combined with light in the management of cancer is known as photodynamic therapy. Porphyrin derivatives are the major class of chemicals that have been studied in this regard. Unfortunately, the porphyrin mixture dihematoporphyrin ethers known as Photofrin II suitable for photodynamic therapy possesses several intrinsic disadvantages which led to a search for new photosensitizers with improved therapeutic effects and low phototoxicity. Phthalocyanines have shown some promise in this regard. The purpose of the studies outlined in this proposal is to develop new knowledge regarding the potential usefulness of phthalocyanines in photodynamic therapy of murine skin neoplasms. Virtually no studies have been conducted to define the photodynamic therapy and photosensitization and/or phototoxic effects of phthalocyanines in the skin. In addition we have chosen skin tumors because of extensive experience of this laboratory, because unlike tumor implant systems they develop in their own matrix, because regression of multiple tumors as a function of time can be monitored in the same animal and because same animal can serve as its own control. Tetrasulfonated chloroaluminum phthalocyanine and selected new well defined structures will be synthesized and will be used as the prototype to define their pharmacodynamic and phototoxic effects in normal murine skin and in benign papillomas and squamous cell carcinomas induced by chemical carcinogens in mouse skin in vivo in assay procedures operational in this laboratory. Promising phthalocyanines will be studied to ensure that they possess no or low dark toxicity in the animals. Based on these studies we will select the most promising phthalocyanine for detailed mechanistic studies. The mechanism of phthalocyanine action will be studied in cultured murine keratinocytes and fibroblasts as well as in human keratinocytes and in human epidermoid carcinoma cell line A 431 in vitro to complement and further expand the data obtained from the animal studies. The role of reactive oxygen species in this process including superoxide anion, 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 action 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 malignant neoplasms in the skin.
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