Mitochondria! Alterations in Photodynamic Therapy-resistant Cells1

The characterization of radiation-induced fibrosarcoma cells (RIF-8A) which have been selected for resistance to Photofrin-mediated photodynamic therapy (PDT) is detailed in this report. Morphological and func tional assessment of mitochondria in both the resistant RIF-8A and pa rental RIF-I cells show distinct differences. Electron micrographs show that the mitochondria in the RIF-8A cells are relatively smaller, stain more densely, and display a higher cristae density than RIF-1 cells. P. A. An drews el al. (Cancer Res., 52: 1895-1901, 1992) reported similar mito chondria! differences between a human ovarian carcinoma cell line, 2008, and its cisplatin-resistant counterpart (C13*). Dose-response curves dem onstrate that these cisplatin-resistant C13* cells show cross-resistance to Photofrin-mediated PDT. Functionally, the RIF-8A cells produce more ATP and demonstrate higher succinate dehydrogenase activity than do the RIF-1 cells, but the rates of oxygen consumption do not differ between the two cell types. The PDT-sensitive RIF-1 cells demonstrate a significantly higher susceptibility to inhibition of glycolytic activity as determined by 2-deoxy-</-glucose survival curves. These findings suggest differences in the efficacy and/or mode(s) of energy production in the RIF-1 and RIF-8A cells. Since mito chondria are sensitive targets for porphyrin-mediated PDT, the observed changes in mitochondria! structure and/or function may be involved in the PDT resistance seen in RIF-8A cells. Biochemical determinations of succinate dehydrogenase activity, an enzyme in the electron transport chain, and susceptibility to the inhi bition of glycolytic activity were also performed to investigate the bioenergetics of the parental RIF-1 and resistant RIF-8A cells.