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Effectiveness of -Aminolevulinic Acid-induced Protoporphyrin as a Photosensitizer for Photodynamic Therapy in Vivo¹

Departments of Biochemistry [Z. H., S. L. G., R. H.], Radiology [T. H. F.], and Biophysics [T. H. F.], and the University of Rochester Cancer Center [T. H. F., R. H.], University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, and the Department of Physics and Astronomy, University of Rochester, Rochester, New York 14627 [T. H. F.]

We examined the effectiveness of systemic administration of -aminolevulinic acid (-ALA) to induce endogenous protoporphyrin as a regimen for use in photodynamic therapy (PDT) of transplanted R3230AC rat mammary adenocarcinomas in vivo. Levels of porphyrins synthesized in various tissues after systemic administration of -ALA differed, with their accumulation in tumor tissue being dependent on both the dose and the time after -ALA administration. Tumor, liver, and intestine contained greater than 3.0 µg porphyrin/g tissue at 3 h after -ALA injection, whereas porphyrin levels in rat skin and muscle at that time were an order of magnitude lower. Analysis of tissues by HPLC revealed that the predominant porphyrin synthesized in tumors was protoporphyrin IX, whereas in liver, 18% of the total porphyrin detected was protoporphyrin IX, and in muscle, it was undetectable. Time-dependent studies of the uptake of ¹⁴C label from -ALA into the various tissues were not predictive of either the total amount of porphyrin or which porphyrin species would be present at 3 h after -ALA injection. Additionally, no simple relationship was apparent between the activities of certain selected enzymes involved in heme biosynthesis and the concentrations of porphyrins in the different tissues. High levels of tumor protoporphyrin IX were sustained by administration of two sequential doses of -ALA, at 3.0 and 1.5 h prior to irradiation. Using these treatment conditions, we inhibited R3230AC growth to an extent that was comparable to that obtained for Photofrin®-induced PDT. High energy phosphate metabolism, measured by nuclear magnetic resonance spectroscopy in vivo, was dramatically impaired after -ALA-based PDT, with tumor ATP levels reduced to near zero by 4 h after irradiation. Our results demonstrate that -ALA-based PDT may be an alternative to current treatment protocols that use exogenously administered photosensitizers.

¹ Supported by USPHS Grant CA36856 (National Cancer Institute, NIH).

² Submitted in partial fulfillment for the Ph.D. degree.

³ To whom requests for reprints should be addressed, at Department of Biochemistry, Box 607, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642.

Received 12/27/94. Accepted 2/16/95.

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