MECHANISMS OF PORPHYRIN ACCUMULATION BY CANCEROUS CELLS

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Porphyrin phototherapy has been used with some success to treat certain neoplasias, including otherwise inoperable cancers of the bronchus. Prophyrins accumulated in cancerous cells when illuminated fluoresce, enabling detection of porphyrin-loaded cancerous cells and also produce localized tumoricidal effects. The biochemical mechanisms and consequences of porphyrin interactions with cellular components of normal and cancerous tissues have not been fully assessed. Porphyrin-binding proteins and porphyrin-metabolizing enzymes are likely to be important factors in the cellular accumulation or elimination of porphyrins acting either as "trapping reservoirs" or altering the metabolism of exogenous porphyrins. Moreover, by interacting with important cellular components, exogenous porphyrins are likely to affect normal tissues. One aim is to identify and quantitate cellular prophyrin-binding proteins in normal and neoplastic tissues. The initial focus will be on the cytosolic glutathione-S-transferases since several porphyrins used clinically inhibit these enzymes. The proteins involved will be isolated by affinity chromatography and used to raise antibodies for subsequent identification and quantitation in the tissues of interest. Another aim is to evaluate the metabolism of exogenous porphyrins. Intracellular metabolism of porphyrins is likely to affect their retention by cells since porphyrins would tend to accumulate in tissues which cannot readily metabolize them. Differential effects of exogenous porphyrins on mitochondrial ferrochelatase and considerably lower levels of this enzyme in Morris hepatoma 7288 C tissue than normal liver have been found. The interaction of exogenous porphyrins with ferrochelatase and of their heme-analogs with heme oxygenase, and the activity of these enzymes in normal and cancerous tissues will be measured. The effects on cellular metabolism of exposure of normal cells to exogenous porphyrins will also be assessed. The Morris hepatoma is used as a model system because these cells can be grown in culture or as a solid tumor in rats. In addition, they are liver-derived cells and their metabolism can be compared with normal liver, which plays a vital role in porphyrin metabolism. A prime objective is to carry out similar research with human tumors based on the knowledge and tools developed in the studies with the rat.