Mitochondria as the target organelle for protoporphyrin IX (PPIX) accumulation and toxicity in photodynamic diagnosis (PDD) and photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA)
René C. KriegJoachim RauchEsther EndlicherSabine DietrichJuergen SchöelmerichFerdinand HofstaedterRuth KnuechelHelmut Messmann
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The quantification of the induced fluorescence in tumor tissue is important to design optical equipment for photodynamic diagnosis (PDD). The fluorescence intensities of Protoporphyrin IX (PpIX) solved in Dimethylsulfoxid and induced via application of Aminolevulinic Acid in cells, cultivated in the hen's eggs model, have been measured photometrically. With an optimized CCD-camera-systems fluorescent tumor areas were detected before and after photodynamic therapy (PDT). The ratio of dead cells was detected by staining with trypan blue after PDT. The measurements were carried out with various energy densities at the time of maximal PpIX-enrichement.
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Recently we published the article ‘Accumulation of protoporphyrin IX in medulloblastoma cell lines and sensitivity to subsequent photodynamic treatment’. In this commentary, we review protoporphyrin IX accumulation after application of 5-aminolaevulinic acid and the resulting sensitivity of medulloblastoma cells to photodynamic therapy.
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Abstract Photodynamic therapy using 5‐aminolevulinic acid is a treatment method in which the fluorescent substance of protoporphyrin IX excessively accumulated specifically in cancer cells is excited by visible red or green light irradiation, and reactive oxygen is produced and injures cancer cells. Photodynamic therapy using 5‐aminolevulinic acid less markedly influences the surrounding normal cells and tissue as a result of no accumulation of protoporphyrin IX , being a low‐invasive, less harmful treatment localized to cancer. Furthermore, photodynamic therapy using 5‐aminolevulinic acid is painless, requiring no anesthesia because localized lesions are treated at a low‐energy level, and repeatedly applicable, unlike radiotherapy, and so is expected to be a new low‐invasive treatment based on a concept completely different from existing treatments. In fact, photodynamic therapy using 5‐aminolevulinic acid for bladder cancer was clinically demonstrated mainly for treatment‐resistant bladder carcinoma in situ , and favorable outcomes have been obtained. Photodynamic therapy using 5‐aminolevulinic acid are photodynamic technologies based on the common biological characteristic of cancers, and are expected as novel therapeutic strategies for many types of cancer.
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Protoporphyrin IX (PpIX) displays high tumour-selective uptake following oral administration of 5-aminolaevulinic acid (ALA), a fact that is being exploited for the fluorescence-guided resection (FGR) and photodynamic therapy (PDT) of human brain malignancies. A clinical procedure for interstitial PDT (iPDT) has been established including pre-treatment planning, optical fiber insertion under stereotactic guidance and therapeutic irradiation at non-thermal fluence rates. We have previously reported on median survival in the range of 15 months and the existence of some intriguing long-term survivors (>5 years) following iPDT. Such successful treatments rely on for example sufficient light, PpIX and oxygen levels. We have investigated the absolute PpIX concentration as well as the PDT-induced photobleaching kinetics in brain tissues. Tissue samples acquired during FGR contained PpIX concentrations up to 28 μM. This observation implies that ALA-induced PpIX levels are sufficient for inducing PDT effects in viable tumour tissue upon therapeutic irradiation. However, regions of pre-existing necrosis were characterised by significantly lower photosensitiser levels. Fluorescence spectroscopy was implemented in parallel to iPDT with the aim to employ PpIX photobleaching as a tool for realtime treatment supervision and early treatment prognosis.
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Photodynamic therapy (PDT) with methyl aminolevulinate (MAL) is a popular treatment for actinic keratoses (AK), and several PDT treatment modalities with similar cure rates are in use. The effect relies on the activation of protoporphyrin IX (PpIX) in premalignant cells. This study aimed to measure PpIX during each treatment modality to determine the minimal PpIX activation and shortest exposure time for optimal cure rate. In four different treatment modalities, we established the PpIX formation up to three hours after MAL application without illumination and measured the speed of PpIX photoactivation during 9 min of red light (37 J/cm2). The level of PpIX three hours after MAL application was set to 100 PpIX units. In comparison, 85 PpIX units were formed during daylight PDT, 57 PpIX units during pulse PDT, and 52 PpIX units without any curettage prior to MAL. The activation of 50 PpIX units should, therefore, be enough to obtain a full effect on AK. Further, red light illumination may be shortened from 9 min to 1–2 min. The results indicate that PDT can be performed successfully with half the illumination time used in daylight PDT today and with one fourth of the illumination time used in classical PDT.
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With current treatment methods the prognosis for patients with aggressive brain tumors is dismal. Treatment failure is usually due to local recurrence of tumor. Intra-operative photodynamic detection (PDD) of tumor tissue and post-surgical photodynamic therapy (PDT) of the resection cavity may be of benefit. The utility of 5-aminolevulinic acid (ALA) has been recognized in many different treatment fields over the past decade. Following administration of exogenous ALA, the endogenous photosensitizer, protoporphyrin IX (PpIX), accumulates in tumor tissue. A photodynamic effect occurs upon light activation of the target tissue. This article reviews the current preclinical and clinical studies and potential future applications of ALA and its ester-induced PpIX as a photosensitizing agent in the detection and treatment of brain tumors.
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