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Photodynamic Therapy-mediated Oxidative Stress Can Induce Expression of Heat Shock Proteins¹

Clayton Ocular Oncology Center, Childrens Hospital Los Angeles, and Departments of Pediatrics [C. J. G.], Radiation Oncology [C. J. G.], and Molecular Pharmacology and Toxicology [S. R., C. J. G.], University of Southern California, Los Angeles, California 90027

Photodynamic therapy (PDT) is an experimental cancer therapy inducing tumor tissue damage via photosensitizer-mediated oxidative cytotoxicity. A previous report indicates that oxidative stress induced by hydrogen peroxide or menadione activates the heat shock transcription factor in mouse cells but does not result in either increased transcription or translation of heat shock proteins (HSPs). Our study documents that photosensitizer-mediated oxidative stress can activate the heat shock factor as well as increase HSP-70 mRNA and protein levels in mouse RIF-1 cells. The cellular heat shock response after PDT varied for the different photosensitizers being examined. Treatments using either a chlorin (mono-L-aspartyl chlorin-e6)- or purpurin (tin etio-purpurin)-based sensitizer induced HSP-70 expression, whereas identical photosensitization conditions with a porphyrin (Photofrin)-based sensitizer failed to induce a cellular HSP response. These sensitizers, which generate singlet oxygen as the primary oxidant during photosensitization, were used in experiments under isoeffective treatment conditions. HSP-70 expression after photosensitization was associated with the concomitant induction of thermotolerance in PDT-treated cells. Interestingly, reverse transcription-PCR demonstrated that in vivo PDT treatments of RIF-1 tumors induce expression of HSP-70 for all photosensitizers including Photofrin. These results indicate that photosensitizer-generated singlet oxygen exposure can induce in vitro and in vivo HSP-70 expression, and that specific subcellular targets of PDT (which can differ for various sensitizers) are determinants for HSP-70 activation after oxidative stress.

¹ This research was performed in conjunction with the Clayton Foundation for Research and was supported in part by USPHS Grant R37-CA-31230 from NIH and Office of Naval Research Grant N000014-91-J-4047 from the Department of Defense.

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

³ Present address: Swiss Institute for Experimental Cancer Research, 155 Chemin des Boveresses, Epalinges, CH-1066, Switzerland.

Received 1/12/96. Accepted 3/19/96.

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