The influence of iron chelators on the accumulation of protoporphyrin IX in 5-aminolaevulinic acid-treated cells

Berg, Kristian; Anholt, Helle; Bech, Øystein; Moan, Johan Emelian

doi:10.1038/bjc.1996.423

Cited by 137 publications

(129 citation statements)

References 34 publications

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“…Only a 3-fold increase in PpIX fluorescence was observed in WiDr cells co-incubated with ALA and DFO while a 30-fold increase was observed with the same parameters in V79 cells [21]. Similarly large differences in enhancement were observed with CP94 in a study reported by Bech et al This would not be expected from a standard Metvix ® -PDT protocol with these thicker nodular BCCs, where prior de-bulking and two treatments 7 days apart would normally be require to achieve this result.…”

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

“…The ability of EDTA and DFO or alternately, CP94 and DFO to enhance PpIX photosensitizer accumulations have been directly compared in vitro [21,24]. DFO was found to be superior to EDTA in this role [21] and CP94 was found to be superior to DFO for this purpose [24]. Therefore the likely order of efficacy of these chelating agents for the enhancement of PDT has been proposed as: CP94>DFO>EDTA (although CP94 and EDTA have not been directly compared) [24].…”

Section: Introductionmentioning

confidence: 99%

“…Several authors have now investigated this technique of enhancement in vitro using ethylenediamine tetraacetic acid (EDTA) [21,11], desferrioxamine (DFO) [21,22] and the novel hydroxypyridinone iron chelator CP94 [23,24]. The ability of EDTA and DFO or alternately, CP94 and DFO to enhance PpIX photosensitizer accumulations have been directly compared in vitro [21,24].…”

Section: Introductionmentioning

confidence: 99%

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Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma

Pye

Campbell

Curnow

2008

J Cancer Res Clin Oncol

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Purpose:Methyl-aminolevulinate (MAL) photodynamic therapy (PDT) is a cancer therapy that combines the selective accumulation of a photosensitizer in tumor tissue with visible light (and tissue oxygen) to produce reactive oxygen species. This results in cellular damage and ablation of tumor tissue. Combining iron chelators with MAL has the potential to increase the accumulation of the photosensitizer protoporphyrin IX (PpIX) by reducing its bioconversion to heme. This paper investigates this method of enhancement both in vitro and for the first time clinically for the treatment of nodular basal cell carcinoma (BCC). Methods:Enhancement of MAL-induced PpIX accumulation by the iron chelator CP94 was quantified fluorometrically in human cultured cells (including three dermatological cell types). An open, dose-escalating, pilot study was then conducted in patients with nodular BCC, to determine the safety of this pharmacological modification. Results:Large enhancements in PpIX accumulation were observed in the cultured cells when coincubated with the iron chelator CP94. Clinically the addition of CP94 was found to be feasible and safe. In addition greater reductions in tumor depth were observed in the CP94 coincubated tumors. Conclusion:Iron chelation by CP94 is an effective enhancer of MAL-induced PpIX accumulation in vitro.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma

Pye

Campbell

Curnow

2008

J Cancer Res Clin Oncol

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“…This result suggested that TSCs did not affect heme synthesis by iron chelation as suggested in many publications. 23,24 The decrease of ferrochelatase expression in HCT 116 cells 25,26 can be one of the factors influencing this atypical behavior.…”

mentioning

confidence: 99%

Iron Chelators in Photodynamic Therapy Revisited: Synergistic Effect by Novel Highly Active Thiosemicarbazones

Mrozek-Wilczkiewicz

Serda

Musioł

et al. 2014

ACS Med. Chem. Lett.

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In photodynamic therapy (PDT), a noninvasive anticancer treatment, visible light, is used as a magic bullet selectively destroying cancer cells by a photosensitizer that is nontoxic in the dark. Protoporphyrin IX (PpIX) is a natural photosensitizer synthesized in the cell, which is also a chelating agent that if bonded to Fe 2+ forms heme, a central component of hemoglobin. Therefore, xenobiotic iron chelators can disturb iron homeostasis, increasing the accumulation of PpIX, obstructing the last step of heme biosynthesis, and enhancing PDT efficiency. However, the attempts to use this promising idea have not proved to be hugely successful. Herein, we revisited this issue by analyzing the application of iron chelators highly toxic in the dark, which should have higher Fe 2+ affinity than the nontoxic chelators used so far. We have designed and prepared thiosemicarbazones (TSC) with the highest dark cellular cytotoxicity among TSCs ever reported. We demonstrate that compound 2 exerts powerful PDT enhancement when used in combination with 5-aminolevulinic acid (ALA), a precursor of PpIX.

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Effects of the inhibitors of energy metabolism, lonidamine and levamisole, on 5-aminolevulinic-acid-induced photochemotherapy

et al. 1996

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The ability of endogenously synthesized protoporphyrin IX (PplX) to damage Chinese hamster lung fibroblasts of the line W 9 by exposure to light was examined. This treatment induced reduction of cellular ATP, GTP, of the NADH/NAD+ ratio and of oxygen consumption. The present results indicate a close relationship between inhibition of respiration of irradiated cells and their ability to survive, e.g. I min of light exposure induced 90% inhibition of oxygen consumption and inactivation of approximately 95% of the cells, while the cellular content of ATP was reduced by only 15%. This indicates that the mitochondria are one of the primary targets of 5-aminolevulinic acid (ALA)-mediated photochemotherapy (PCT). In the present study, ALA-PCT was combined with the modulators of the glycolysis and the respiration chain, levamisole (LEV) and lonidamine (LND). A synergistic effect of combining ALA-PCT with non-toxic concentrations of LND was observed when LND was given prior to light exposure. This synergism was observed despite a substantial LND-induced inhibition of PplX formation. At increasing doses of LND (>0.15 mM) the combination treatment becomes less efficient. This is due to the inhibition of PplX synthesis induced by LND. A synergistic effect of ALA-PDT and LEV was found when LEV was given prior to light exposure. This was at least partly due to an LEV-stimulated effect on ALA-induced PplX formation. However, it is not clear from the present results whether LEV may perturb energy metabolism in W 9 cells since LEV alone did not reduce the energy charge or the NADH/NAD+ ratio. When LEV or LND were given after ALA-PCT, these 2 treatment modalities acted in an additive or slightly synergistic manner.o 1996 Wilqv-Liss, Inc.

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The influence of iron chelators on the accumulation of protoporphyrin IX in 5-aminolaevulinic acid-treated cells

Cited by 137 publications

References 34 publications

Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma

Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma

Iron Chelators in Photodynamic Therapy Revisited: Synergistic Effect by Novel Highly Active Thiosemicarbazones

Effects of the inhibitors of energy metabolism, lonidamine and levamisole, on 5-aminolevulinic-acid-induced photochemotherapy

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