Augmentation of 5-Aminolevulinic Acid Treatment of Glioblastoma by Adding Ciprofloxacin, Deferiprone, 5-Fluorouracil and Febuxostat: The CAALA Regimen

Kast, Richard E.; Skuli, Nicolas; Sardi, Iacopo; Capanni, Felix; Heßling, Martin; Fròsina, Guido; Kast, Anton; Karpel‐Massler, Georg; Halatsch, Marc Eric

doi:10.3390/brainsci8120203

Cited by 17 publications

(11 citation statements)

References 68 publications

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“…A total of four compounds (Table 1) were approved by the FDA for the indication glioblastoma. Three of them were therapeutic compounds, one is 5-aminolevulinic acid which is a photo-diagnostic substance for the intraoperative detection of resection margins [11]. These results were in line with the findings of the FDALabel database query: bevacizumab, carmustine, and temozolomide list the indication "glioblastoma" on their FDA approved labels.…”

Section: Approved Drugs For Glioblastomasupporting

confidence: 77%

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The drug development pipeline for glioblastoma—A cross sectional assessment of the FDA Orphan Drug Product designation database

2021

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Background Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest. Objectives To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM. Methods Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected. Results Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline. Conclusion Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

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Section: Approved Drugs For Glioblastomasupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

The drug development pipeline for glioblastoma—A cross sectional assessment of the FDA Orphan Drug Product designation database

2021

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“…Further experimentation on the effect of 5-ALA alone or in combination with other substances or therapies that enhances intracellular PP-IX on tumor cells is required. It has been shown that several compounds, such as vitamin D, ciprofloxacin, deferiprone, and febuxostat, as well as different adjuvant therapies, such as photodynamic therapy and ionizing irradiation, augment the cytotoxicity of 5-ALA in tumoral cells [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effects of 5-Aminolevulinic Acid on Human Malignant Glioblastoma Cells

Jalili‐Nik

Abbasinezhad-Moud

Negah

et al. 2021

IJMS

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5-Aminolevulinic acid (5-ALA) is a naturally occurring non-proteinogenic amino acid, which contributes to the diagnosis and therapeutic approaches of various cancers, including glioblastoma (GBM). In the present study, we aimed to investigate whether 5-ALA exerted cytotoxic effects on GBM cells. We assessed cell viability, apoptosis rate, mRNA expressions of various apoptosis-related genes, generation of reactive oxygen species (ROS), and migration ability of the human U-87 malignant GBM cell line (U87MG) treated with 5-ALA at different doses. The half-maximal inhibitory concentration of 5-ALA on U87MG cells was 500 μg/mL after 7 days; 5-ALA was not toxic for human optic cells and NIH-3T3 cells at this concentration. The application of 5-ALA led to a significant increase in apoptotic cells, enhancement of Bax and p53 expressions, reduction in Bcl-2 expression, and an increase in ROS generation. Furthermore, the application of 5-ALA increased the accumulation of U87MG cells in the SUB-G1 population, decreased the expression of cyclin D1, and reduced the migration ability of U87MG cells. Our data indicate the potential cytotoxic effects of 5-ALA on U87MG cells. Further studies are required to determine the spectrum of the antitumor activity of 5-ALA on GBM.

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“…Additionally, other FDA approved medications increase PpIX accumulation in tumor cells, including iron chelators (deferoxamine and deferiprone), vitamin D, ciprofloxacin, 5-fluorouracil, and febuxostat. Combination of these drugs has been proposed as a means to augment efficacy of 5-ALA in PDT (32).…”

Section: Medications That May Affect Pdt For Glioblastomamentioning

confidence: 99%

Photodynamic Therapy for the Treatment of Glioblastoma

2020

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Glioblastoma is the most common form of adult brain cancer and remains one of the deadliest of human cancers. The current standard-of-care involves maximal tumor resection followed by treatment with concurrent radiation therapy and the chemotherapy temozolomide. Recurrence after this therapy is nearly universal within 2 years of diagnosis. Notably, >80% of recurrence is found in the region adjacent to the resection cavity. The need for improved local control in this region, thus remains unmet. The FDA approval of 5-aminolevulinic acid (5-ALA) for fluorescence guided glioblastoma resection renewed interests in leveraging this agent as a means to administer photodynamic therapy (PDT). Here we review the general principles of PDT as well as the available literature on PDT as a glioblastoma therapeutic platform.

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Augmentation of 5-Aminolevulinic Acid Treatment of Glioblastoma by Adding Ciprofloxacin, Deferiprone, 5-Fluorouracil and Febuxostat: The CAALA Regimen

Cited by 17 publications

References 68 publications

The drug development pipeline for glioblastoma—A cross sectional assessment of the FDA Orphan Drug Product designation database

The drug development pipeline for glioblastoma—A cross sectional assessment of the FDA Orphan Drug Product designation database

Antitumor Effects of 5-Aminolevulinic Acid on Human Malignant Glioblastoma Cells

Photodynamic Therapy for the Treatment of Glioblastoma

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