Porphyrin-sensitized photoradiation therapy (PSPT) is a promising treatment modality for a variety of malignant tumors, and is currently a subject of active research and development in many institutes. The overall goal of our project is to develop PSPT for bladder carcinoma. We have made substantial progress during the past funding period, both in basic studies and in the development of this treatment. The current application will enable us to continue our efforts in achieving this goal. In this application, we intend to concentrate our clinical studies on the development of "whole bladder wall photoradiation" to treat superficial tumors including carcinoma-in-situ (CIS), after sensitizing the tumor with hermatoporphyrin derivative (HpD). The photoradiation will be accomplished by a 514 nm laser light delivered through an optical fiber with a dispersion tip, which when situated at the center of the bladder will distribute the light to illuminate the entire bladder wall. Basic studies will be carried out to elucidate some of the mechanisms of PSPT as a basis for improving the treatment. These will be centered around the theory that molecular aggression and deaggregation play major parts in porphyrin uptake, retention and photosensitization, and the "non-exchangeable" porphyrin (NEP) may be an "in vivo active component" of HpD. Studies will be carried out to investigate the porphyrin composition and the physical state of NEP, the relationship between active HpD component and the formation of NEP, and the possible association of NEP with subcellular sites. Also to be studied are the interactions of plasma and cellular proteins with the porphyrins; the effect of protein binding on porphyrin uptake, retention and formation of NEP, and intracellular proteins associated with NEP. Several pre-clinical studies will also be carried out to explore new approaches of PSPT. These include combination with hyperthermia, use of other types of lasers and light at wavelengths other than nm. This project offers the potential for a new modality in treating recurrent and resistant bladder cancer, some of these cannot be treated satisfactorily at the present. Information gained form the basic studies will provide a better understanding for mechanisms of porphyrin uptake, retention and photosensitization in tumor cells, thus providing a basis for improving the treatment by increasing the efficacy and reducing the side effects. The development and the information can also be useful in the treatment of other tumors by PSPT.