title: Delta-aminolaevulinic acid-induced photodynamic therapy inhibits protoporphyrin IX biosynthesis and reduces subsequent treatment efficacy in vitro.
abstract: Recently, considerable interest has been given to photodynamic therapy of cancer using delta-aminolaevulinic acid to induce protoporphyrin IX as the cell photosensitizer. One advantage of this modality is that protoporphyrin IX is cleared from tissue within 24 h after delta-aminolaevulinic acid administration. This could allow for multiple treatment regimens because of little concern regarding the accumulation of the photosensitizer in normal tissues. However, the haem biosynthetic pathway would have to be fully functional after the first course of therapy to allow for subsequent treatments. Photosensitization of cultured R3230AC rat mammary adenocarcinoma cells with delta-aminolaevulinic acid-induced protoporphyrin IX resulted in the inhibition of porphobilinogen deaminase, an enzyme in the haem biosynthetic pathway, and a concomitant decrease in protoporphyrin IX levels. Cultured R3230AC cells exposed to 0.5 mM delta-aminolaevulinic acid for 27 h accumulated 6.07 x 10(-16) mol of protoporphyrin IX per cell and had a porphobilinogen deaminase activity of 0.046 fmol uroporphyrin per 30 min per cell. Cells cultured under the same incubation conditions but exposed to 30 mJ cm(-2) irradiation after a 3-h incubation with delta-aminolaevulinic acid showed a significant reduction in protoporphyrin IX, 2.28 x 10(-16) mol per cell, and an 80% reduction in porphobilinogen deaminase activity to 0.0088 fmol uroporphyrin per 30 min per cell. Similar effects were evident in irradiated cells incubated with delta-aminolaevulinic acid immediately after, or following a 24 h interval, post-irradiation. There was little gain in efficacy from a second treatment regimen applied within 24 h of the initial treatment, probably a result of initial metabolic damage leading to reduced levels of protoporphyrin IX. These findings suggest that a correlation may exist between the delta-aminolaevulinic acid induction of porphobilinogen deaminase activity and the increase in intracellular protoporphyrin IX accumulation.
authors.affiliation: Department of Biochemistry and Biophysics and the UR Cancer Center, University of Rochester School of Medicine and Dentistry, University of Rochester, NY 14642, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Gibson
authors.forename: J J
authors.initials: JJ
authors.lastname: Havens
authors.forename: M L
authors.initials: ML
authors.lastname: Nguyen
authors.forename: R
authors.initials: R
authors.lastname: Hilf
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D011163:Hydroxymethylbilane Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008027:Light; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011524:Protoporphyrins / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D016896:Treatment Outcome
chemical_list: D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D011163:Hydroxymethylbilane Synthase