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Glucose Regulated Protein Induction and Cellular Resistance to Oxidative Stress Mediated by Porphyrin Photosensitization¹

Clayton Ocular Oncology Center, Childrens Hospital of Los Angeles [C. J. G., A. F., N. R., S. W.]; Kenneth Norris Jr. Comprehensive Cancer Center [C. J. G., A. S. L.], and Departments of Pediatrics [C. J. G.], Radiation Oncology [C. J. G.], Molecular Pharmacology and Toxicology [C. J. G.]; and Biochemistry [A. S. L.], University of Southern California School of Medicine, Los Angeles, California 90027

Photodynamic therapy (PDT) utilizes a tumor localizing porphyrin photosensitizer in the clinical treatment of cancer. At a mechanistic level, porphyrin photosensitization generates reactive oxygen species which initiate oxidative damage to a wide spectrum of biomolecules. Cellular stress proteins are also increased following oxidative stress treatments. In the current study, we examined porphyrin photosensitizing parameters associated with induction of the glucose regulated family of stress proteins. Elevated levels of mRNA encoding glucose regulated proteins (GRPs) as well as increases in GRP protein synthesis were observed for mouse radiation induced fibrosarcoma cells exposed to an extended (16-h) porphyrin incubation prior to light exposure. However, a short (1-h) porphyrin incubation prior to light treatment (designed to produce comparable phototoxicity as PDT using the 16-h porphyrin incubation protocol) was associated with only minimal increases in GRP mRNA levels or GRP protein synthesis. The relationship between GRP levels and PDT sensitivity was examined in radiation induced fibrosarcoma cells pretreated with the calcium ionophore A-23187 in order to overexpress GRPs prior to photosensitization. Resistance to PDT was observed in cells overexpressing GRPs only under photosensitizing conditions associated with the extended porphyrin incubation protocol, and this response was not due to changes in cellular porphyrin uptake. In separate experiments, a transient elevation of GRP mRNA levels was observed in transplanted mouse mammary carcinomas following in vivo PDT treatments. Our results indicate that specific targets of oxidative damage (modulated by porphyrin incubation conditions) instead of generalized cellular exposure to reactive oxygen species are correlated with PDT mediated GRP induction. In this regard, GRP induction may be a useful in vivo biochemical marker of PDT mediated injury. These results also support the hypothesis that GRPs may play a role in modulating sensitivity to cellular stresses including certain types of oxidative injury.

¹ This work was performed in conjunction with the Clayton Foundation for Research and was supported in part by USPHS Grants R37-CA-31230 to C. J. G. and R37-CA-27607 to A. S. L. from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Clayton Ocular Oncology Center, Mail Stop 67, Childrens Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027.

Received 2/22/91. Accepted 10/ 7/91.

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