EFFECTIVENESS OF DELTA-AMINOLEVULINIC ACID-INDUCED PROTOPORPHYRIN AS A PHOTOSENSITIZER FOR PHOTODYNAMIC THERAPY IN-VIVO

We examined the effectiveness of systemic administration of delta-amin olevulinic acid (delta-ALA) to induce endogenous protoporphyrin as a r egimen for use in photodynamic therapy (PDT) of transplanted R3230AC r at mammary adenocarcinomas in vivo. Levels of porphyrins synthesized i n various tissues after systemic administration of delta-ALA differed, with their accumulation in tumor tissue being dependent on both the d ose and the time after delta-ALA administration. Tumor, liver, and int estine contained greater than 3.0 mu g porphyrin/g tissue at 3 h after delta-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 detec ted was protoporphyrin IX, and in muscle, it was undetectable. Time-de pendent studies of the uptake of C-14 label from delta-ALA into the va rious tissues were not predictive of either the total amount of porphy rin or which porphyrin species would be present at 3 h after delta-ALA injection. Additionally, no simple relationship was apparent between the activities of certain selected enzymes involved in heme biosynthes is and the concentrations of porphyrins in the different tissues. High levels of tumor protoporphyrin IX were sustained by administration of two sequential doses of delta-ALA, at 3.0 and 1.5 h prior to irradiat ion. Using these treatment conditions, we inhibited R3230AC growth to an extent that was comparable to that obtained for Photofrin(R)-induce d PDT. High energy phosphate metabolism, measured by nuclear magnetic resonance spectroscopy in vivo, was dramatically impaired after delta- ALA-based PDT, with tumor ATP levels reduced to near zero by 4 h after irradiation. Our results demonstrate that delta-ALA-based PDT may be an alternative to current treatment protocols that use exogenously adm inistered photosensitizers.