Considerable recent interest has arisen for the use of photoradiation therapy as a non-invasive treatment modality in cancer patients. This approach employs the administration of photosensitizing drugs, such as hematoporphyrin derivative (Hpd), allowing the reagent to accumulate in the tumor, and exposing the lesion to photoradiation. Preliminary clinical results are encouraging in breast and lung cancer patients, but much remains to be studied to elucidate the mechanisms whereby tumor regression is induced. Not only is there a need to define the events leading to cytotoxicity, but, since Hpd is a mixture of several known and unknown porphyrin species, there is a need to identify those porphyrin moieties that produce photosensitization. Studies conducted in vitro need to be translated in vivo. We have selected as models for these studies two well-differentiated rodent mammary tumors, which our laboratory has investigated extensively in vivo and in vitro. We have, from prior studies, developed in vitro and in vivo - in vitro assays based on mitochondrial function along with methods to fractionate Hpd into various components, that will enable us to: 1) study the photosensitizing components of Hpd and ascertain their relative potencies on selected enzymes in mitochondria and cytosol involved in respiration and glycolysis, i.e., ATP production; 2) obtain data on the pharmacokinetics of Hpd and its components using a functional in vivo - in vitro assay; 3) determine the optimum power density for cytotoxicity and its relationship to inhibition of selected mitochrondrial and cytoplasmic enzymes in vitro and in vivo; and 4) explore procedures to enhance delivery and/or retention of photosensitizing porphyrin species to tumors, including the use of hormonal perturbations. Results from these studies should provide new insight regarding mechanisms and the species involved, whereby cytotoxicity ensues from porphyrin-induced photosensitization. Studies of pharmacokinetics could lead to development of maneuvers that would improve the efficiency of photoradiation therapy.
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