title: 5-Aminolaevulinic acid-mediated photodynamic therapy in multidrug resistant leukemia cells.
abstract: To verify if photodynamic therapy (PDT) could overcome multidrug resistance (MDR) when it it applied to eradicate minimal residual disease in patients with leukemia, we investigated the fluorescence kinetics of 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) and the effect of subsequent photodynamic therapy on MDR leukemia cells, which express P-glycoprotein (P-gp), as well as on their parent cells. Evaluation of PpIX accumulation by flow cytometry showed that PpIX accumulated at higher levels in mdr-1 gene-transduced MDR cells (NB4/MDR) and at lower levels in doxorubicin-induced MDR cells (NOMO-1/ADR) than in their parent cells. A P-gp inhibitor could not increase PpIX accumulation. Measurement of extracellular PpIX concentration by fluorescence spectrometry showed that P-gp did not mediate the fluorescence kinetics of ALA-induced PpIX production. Assessment of ferrochelatase activity using high-performance liquid chromatography indicated that PpIX accumulation in drug-induced MDR cells was probably regulated by this enzyme. Assessment of phototoxicity of PDT using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that PDT was effective in NB4, NB4/MDR, NOMO-1 and NOMO-1/ADR cells, which accumulated high levels of PpIX, but not effective in K562 and K562/ADR cell lines, which accumulated relatively low levels of PpIX. These findings demonstrate that P-gp does not mediate the ALA-fluorescence kinetics, and multidrug resistant leukemia cells do not have cross-resistance to ALA-PDT.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Hamamatsu University School of Medicine, 3600 Handa-cho, 431-3192, Hamamatsu, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: W J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Ohnishi
authors.forename: I
authors.initials: I
authors.lastname: Yamada
authors.forename: R
authors.initials: R
authors.lastname: Ohno
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D017484:Dermatitis, Phototoxic; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005110:Extracellular Space; D005294:Ferrochelatase / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy; D011524:Protoporphyrins / Q000819:agonists / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D005294:Ferrochelatase