Effectiveness of delta-aminolevulinic acid-induced protoporphyrin as a photosensitizer for photodynamic therapy in vivo.
We examined the effectiveness of systemic administration of delta-aminolevulinic acid (delta-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 delta-ALA differed, with their accumulation in tumor tissue being dependent on both the dose and the time after delta-ALA administration. Tumor, liver, and intestine contained greater than 3.0 micrograms 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 tissue 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 delta-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 delta-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 delta-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 delta-ALA-based PDT, with tumor ATP levels reduced to near zero by 4 h after irradiation. Our results demonstrated that delta-ALA-based PDT may be an alternative to current treatment protocols that use exogenously administered photosensitizers.
Hua
Z
Z
Department of Biochemistry, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Gibson
S L
SL
Foster
T H
TH
Hilf
R
R
D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000622:Aminolevulinic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007700:Kinetics; D008027:Light; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008770:Methylnitrosourea; D051379:Mice; D010778:Photochemotherapy; D011166:Porphyrins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D011524:Protoporphyrins / Q000096:biosynthesis / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D011166:Porphyrins; D011524:Protoporphyrins; D011838:Radiation-Sensitizing Agents; D008770:Methylnitrosourea; D000622:Aminolevulinic Acid