ALA and Malignant Glioma: Fluorescence-Guided Resection and Photodynamic Treatment

Stepp, Herbert; Beck, T.; Pongratz, Thomas; Meinel, Thomas; Kreth, Friedrich-Wilhelm; Tonn, J. C.; Stummer, Walter

doi:10.1615/jenvironpatholtoxicoloncol.v26.i2.110

Cited by 149 publications

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“…without damaging the normal adjacent tissues, Stummer et al first attempted photodynamic diagnostic surgery using 5-aminolevulinic acid (5-ALA) in 1998 and demonstrated that normal brain tissue revealed no porphyrin fluorescence, whereas tumor tissue was distinguished by bright red fluorescence due to the response of glioma to 5-ALA. 28 Currently, fluorescence-guided resection is widely applied, 18,20,25,33 and it has certainly improved the resection rate and prognosis for gliomas. A randomized, controlled, Phase III trial demonstrated that the overall resection rate (65% vs 36%, respectively) and 6-month progression-free survival rate (41% vs 21%, respectively) were significantly improved in the 5-ALA assigned group compared with the control group.…”

mentioning

confidence: 99%

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Suzuki¹,

Wada

Eguchi

et al. 2013

JNS

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Object Gliomas contain aggressive malignant cancer, and resection rate remains an important factor in treatment. Currently, fluorescence-guided resection using orally administered 5-aminolevulinic acid (5-ALA) has proved to be beneficial in improving the prognosis of patients with gliomas. 5-ALA is metabolized to protoporphyrin IX (PpIX) that accumulates selectively in the tumor and exhibits strong fluorescence upon excitation, but glioma cells do not always respond to 5-ALA, which can result in incomplete or excessive resection. Several possible mechanisms for this phenomenon have been suggested, but they remain poorly understood. To clarify the probable mechanisms underlying the variable induction of fluorescence and to improve fluorescence-guided surgery, the authors searched for key negative regulators of fluorescent signal induced by 5-ALA. Methods A comprehensive gene expression analysis was performed using microarrays in 11 pairs of tumor specimens, fluorescence-positive and fluorescence-negative tumors, and screened genes overexpressed specifically in fluorescence-negative tumors as the possible candidates for key negative regulators of 5-ALA–induced fluorescence. The most possible candidate was selected through annotation analysis in combination with a comparison of expression levels, and the relevance of expression of the selected gene to 5-ALA–induced fluorescence in tumor tissues was confirmed in the quantified expression levels. The biological significance of an identified gene in PpIX accumulation and 5-ALA–induced fluorescence was evaluated by in vitro PpIX fluorescence intensity analysis and in vitro PpIX fluorescence molecular imaging in 4 human glioblastoma cell lines (A1207, NMCG1, U251, and U373). Knockdown analyses using a specific small interfering RNA in U251 cells was also performed to determine the mechanisms of action and genes working as partners in the 5-ALA metabolic pathway. Results The authors chose 251 probes that showed remarkably high expression only in fluorescent-negative tumors (median intensity of expression signal > 1.0), and eventually the cadherin 13 gene (CDH13) was selected as the most possible determinant of 5-ALA–induced fluorescent signal in gliomas. The mean expression level of CDH13 in the fluorescence-negative gliomas was statistically higher than that in positive ones (p = 0.027), and knockdown of CDH13 expression enhanced the fluorescence image and increased the amount of PpIX 13-fold over controls (p < 0.001) in U251 glioma cells treated with 5-ALA. Comprehensive gene expression analysis of the CDH13-knockdown U251 cells demonstrated another two genes possibly involved in the PpIX biosynthesis: ATP-binding cassette transporter (ABCG2) significantly decreased in the CDH13 knockdown, while oligopeptide transporter 1 (PEPT1) increased. Conclusions The cadherin 13 gene might play a role in the PpIX accumulation pathway and act as a negative regulator of 5-ALA–induced fluorescence in glioma cells. Although further studies to clarify the mechanisms of action in the 5-ALA metabolic pathway would be indispensable, the results of this study might lead to a novel fluorescent marker able to overcome the obstacles of existing fluorescence-guided resection and improve the limited resection rate.

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confidence: 99%

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Suzuki¹,

Wada

Eguchi

et al. 2013

JNS

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“…In 2006 this same author reported a multicenter phase III trial comparing FIGS to placebo and found 64% complete surgical excision with fluorescence guided resection compared to 38% complete excision in the placebo group 27 . In 2007 Stepp and colleagues reported similar findings with GTR in 65% of patients undergoing FIGS compared to 36% in placebo group 28 . They also demonstrated improved 6 month progression free survival in 41% of patients in the study group vs 21% in the control group.…”

Section: Florescence Guided Resectionmentioning

confidence: 77%

Innovative Surgical Management of Glioma

Seecharan¹,

Pollack²,

Farassati³

2012

Novel Therapeutic Concepts in Targeting Glioma

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“…The nonfluorescent PS precursor 5-aminolevulinic acid (5-ALA, trade name Levulan®) enhances the intrinsic production of protoporphyrin IX (PPIX) in mitochondria, which is activated by light illumination (~ 635 nm) following accumulation at the treatment site leading to the effective generation of reactive oxygen species within treated cells and triggering cell death [17,68,69]. The clinical use of topically applied 5-ALA for PDT was first introduced in 1990 [70] and followed by a wide range of clinical and preclinical studies for the PDT treatment of bladder cancer [71][72][73], chronic polyarthritis [74], malignant glioma [75], nonmelanoma skin cancers such as actinic keratosis (in combination with fluorescence dosimetry) [69,76], Barret's oesophagus and even multidrug resistant leukemia, the latter without much success [77]. In 2013 Bader et al reported a clinical trial using hexaminolevulinate (HAL), a 5-ALA derivative, for the PDT of bladder cancer in humans.…”

Section: Progress In Photosensitizer (Ps) Developmentmentioning

confidence: 99%

New Approaches to Photodynamic Therapy from Types I, II and III to Type IV Using One or More Photons

Scherer

Bisby²,

Botchway³

et al. 2017

ACAMC

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Photodynamic therapy (PDT) is an alternative cancer treatment to conventional surgery, radiotherapy and chemotherapy. It is based on activating a drug with light that triggers the generation of cytotoxic species that promote tumour cell killing. At present, PDT is mainly used in the treatment of wet age-related macular degeneration, for precancerous conditions of the skin (e.g. actinic keratosis) and in the palliative care of advanced cancers, for instance of the bladder or the oesophagus. Due to a lack of phase III clinical trials and limitations of light penetration to deeper lying tumours (in excess of 1 cm), PDT is still not used as a first line cancer treatment, which is surprising given the first clinical trials by Dougherty's group dating back to the 1970's. However research continues to demonstrate the potential benefits of PDT and the need to stimulate funding and uptake of clinical studies using next generation photosensitizers offering advanced targeted delivery, improved photodynamic dose combined with modern light delivery technologies. This review surveys the available PDT treatments and emerging novel developments in the field with a particular focus on two-photon techniques that are anticipated to improve the effectiveness of PDT in tissues at depth and on next generation drugs that work without the need of the presence of oxygen for photosensitization making them effective where hypoxia has taken hold.

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ALA and Malignant Glioma: Fluorescence-Guided Resection and Photodynamic Treatment

Cited by 149 publications

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Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Innovative Surgical Management of Glioma

New Approaches to Photodynamic Therapy from Types I, II and III to Type IV Using One or More Photons

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