Brain Cancer / Glioblastoma

Photodynamic efficacy and spectroscopic properties of 5-ALA-induced protoporphyrin IX in human glioblastoma cells

Author(s): Reinhard Sailer; Wolfgang S. Strauss; Helmut Emmert; Michael Wagner; Rudolf Steiner; Herbert Schneckenburger

Abstract
One of the most promising clinical applications of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PP IX) is the fluorescence diagnosis and photodynamic treatment of malignant brain tumours. In order to obtain a deeper understanding of the cellular processes involved, U373-MG human glioblastoma cells were used as model system to study intracellular location, fluorescence properties and light-induced reactions of the photosensitizer. In comparison with ovarian cancer or breast cancer cell lines, glioblastoma cells accumulated PP IX only to a moderate extent, but were most effectively inactivated (highest photodynamic efficacy per photosensitizer molecule). In contrast to breast cancer cells, which showed a rather granular PP IX fluorescence pattern, PP IX fluorescence in U373-MG cells seemed to originate mainly from cellular membranes. In addition, photobleaching and lowering of fluorescence lifetimes during irradiation were comparably small for this cell line. Combining the results of fluorescence lifetime imaging microscopy (FLIM) and photobleaching measurements, we deduced that those cellular sites where PP IX fluorescence was most pronounced, contributed rather little to its photodynamic efficacy.

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5-Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cells

Author(s): Surajit Karmakara, Naren L. Banika, Sunil J. Patela and Swapan K. Ray

Abstract
Glioblastoma is the most common astrocytic brain tumor in humans. Current therapies for this malignancy are mostly ineffective. Photodynamic therapy (PDT), an exciting treatment strategy based on activation of a photosensitizer, has not yet been extensively explored for treating glioblastoma. We used 5-aminolevulinic acid (5-ALA) as a photosensitizer for PDT to induce apoptosis in human malignant glioblastoma U87MG cells and to understand the underlying molecular mechanisms. Trypan blue dye exclusion test showed a decrease in cell viability after exposure to increasing doses of 5-ALA for 4 h followed by PDT with a broad spectrum blue light (400550 nm) at a dose of 18 J/cm2 for 1 h and then incubation at 37 C for 4 h. Following 0.5 and 1 mM 5-ALA-based PDT (5-ALA-PDT), Wright staining and ApopTag assay showed occurrence of apoptosis morphologically and biochemically, respectively. After 5-ALA-PDT, down regulation of nuclear factor kappa B (NF?B) and baculovirus inhibitor-of-apoptosis repeat containing-3 (BIRC-3) protein indicated inhibition of survival signals. Besides, 5-ALA-PDT caused increase in Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF). Activation of calpain, caspase-9, and caspase-3 occurred in course of apoptosis. Calpain and caspase-3 activities cleaved a-spectrin at specific sites generating 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. The results suggested that 5-ALA-PDT induced apoptosis in U87MG cells by suppression of survival signals and activation of proteolytic pathways. Thus, 5-ALA-PDT can be an effective strategy for inducing apoptosis in glioblastoma.

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Brain Tumour

The majority of brain tumours treated at our division are brain metastasis, malignant glioma and meningioma. The division takes a leading role in adjuvant chemotherapeutic therapy for malignant glioma and we are developing the use of molecular markers (e.g., MGMT methylation status, chromosomal deletion) in the prediction of treatment response. Two ongoing clinical trials on adjuvant chemotherapy for patients with glioblastoma multiforme (GBM). We work closely with the Division of Head and Neck Surgery, and the Division of Plastic and Reconstruction Surgery in treating skull base tumour and we have acquired extensive experience in craniofacial resection for anterior skull base lesions such as olfactory neuroblastoma and recurrent head and neck cancer.

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Allegheny General Hospital has been approved to use a drug that helps neurosurgeons extract tumors

Abstract
Allegheny General Hospital in Pittsburgh has been FDA approved for the use of an experimental drug called 5-aminolevunilic acid (5-ALA) that is used to illuminate and locate brain tumors using UV light. This drug and many other protoporphyrin-like compounds have been used to destroy cancer cells in photodynamic therapy in the past 30 years.

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Photodynamische Therapie (PDT) mit 5-ALA in Glioblastom-Stammzellkulturen

Author(s): C. Ewelt, N. Etminan, S. Jauernik, H.-J. Steiger, W. Stummer

Objective
Considerable attention is being focussed on basic and translational research concerning glioblastoma stem cells, their tumorigenic potential and their resistance to radio- and chemotherapy. 5-ALA based photodynamic therapy (PDT) induces cell death in the C6 glioma spheroid model and appears to improve clinical outcome in patients suffering from recurrent glioblastoma by causing long-sustaining responses. In order to study the acute effects of ALA/PDT on mulitpotent glioblastoma cell lines, we used a three-dimensional cell culture system.

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