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Hematoporphyrin Derivative-induced Photosensitivity of Mitochondrial Succinate Dehydrogenase and Selected Cytosolic Enzymes of R3230AC Mammary Adenocarcinomas of Rats¹

Department of Biochemistry [R. H., P. B. L., S. L. G] and University of Rochester Cancer Center [R. H.], University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

The photosensitizing activity of hematoporphyrin derivative (HPD) was investigated by studying selected enzymes localized to mitochondria and cytosol of R3230AC mammary adenocarcinomas. Experiments in vitro demonstrated that mitochondrial succinate dehydrogenase was inhibited in a drug dose- and light exposure time-related manner; at 7.0 µg of HPD per ml or higher, enzyme activity was inhibited >50% after 15 min of photoradiation. The three cytosol enzymes studied under the same conditions in vitro demonstrated different photosensitivities. Pyruvate kinase activity was significantly inhibited in a dose- and time-related fashion, whereas lactate dehydrogenase was inhibited to a lesser extent, and glucose phosphate isomerase activity was inhibited only at the highest dose (70 µg of HPD per ml) used. The time-course of these responses was examined with an in vivo-in vitro protocol, consisting of photoradiation of mitochondria and cytosol prepared from tumors obtained at various times (up to 1 week) after a single injection of HPD (80 mg/kg). Pyruvate kinase activity was markedly inhibited at early times returning to initial levels by 48 hr; neither lactate dehydrogenase nor glucose phosphate isomerase was inhibited by this treatment. Mitochondrial succinate dehydrogenase and cytochrome c oxidase activities displayed significant photoradiation-induced inhibitions, with greatest inhibition occurring between 24 and 96 hr after injection of HPD; at 1 week, succinate dehydrogenase activity had returned to its initial level, but cytochrome c oxidase activity remained significantly inhibited. These data suggest that HPD-induced photosensitization of mitochondria may be an important site of action contributing to tumor cell cytotoxicity and regression as a result of photoradiation therapy.

¹ Supported by Contract 04-129-4109-AA from the Standard Oil Company Research Center, Cleveland, OH.

² Supported in part by Grant CA 11198, NIH. To whom requests for reprints should be addressed.

Received 10/ 6/83. Accepted 1/ 6/84.