Real-time in vivo kinetics of protoporphyrin IX after administration of 5-aminolevulinic acid in meningiomas and comparative analyses with glioblastomas

OBJECTIVE 5-Aminolevulinic acid (5-ALA) induces fluorescence in high-grade glioma (HGG), which is used for resection. However, the value of 5-ALA–induced fluorescence in low-grade glioma (LGG) is unclear. Time dependency and time kinetics have not yet been investigated. The purpose of this study was to investigate real-time kinetics of protoporphyrin IX (PpIX) in LGG based on hyperspectral fluorescence-based measurements and identify factors that predict fluorescence. METHODS Patients with grade II gliomas and imaging from which HGGs could not be completely ruled out received 5-ALA at 20 mg/kg body weight 4 hours prior to surgery. Fluorescence intensity (FI) and PpIX concentration (CPpIX) were measured in tumor tissue utilizing a hyperspectral camera. Apparent diffusion coefficient (ADC)–based tumor cell density, Ki-67/MIB-1 index, chromosomal 1p/19q codeletion, and 18F-fluoroethyl-l-tyrosine (18F-FET) PET values and their role for predicting fluorescence were evaluated. RESULTS Eighty-one biopsies from 25 patients were included. Tissues with fluorescence demonstrated FI and CPpIX maxima between 7 and 8 hours after administration. When visible fluorescence was observed, peaks of FI and CPpIX were observed within this 7- to 8-hour time frame, regardless of any MRI gadolinium contrast enhancement. Gadolinium enhancement (p = 0.008), Ki-67/MIB-1 index (p < 0.001), 18F-FET PET uptake ratio (p = 0.004), and ADC-based tumor cellularity (p = 0.017) significantly differed between fluorescing and nonfluorescing tissue, but not 1p/19q codeletions. Logistic regression demonstrated that 18F-FET PET uptake and Ki-67/MIB-1 index were independently related to fluorescence. CONCLUSIONS This study reports a fluorescence-based assessment of CPpIX in human LGG tissues related to 18F-FET PET uptake and Ki-67/MIB-1. As in HGGs, fluorescence in LGGs peaked between 7 and 8 hours after 5-ALA application, which has consequences for the timing of administration.

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In Vivo Pharmacokinetics of δ-Aminolevulinic Acid–Induced Protoporphyrin IX During Pre- and Post-Photodynamic Therapy in 7,12-Dimethylbenz(a)nthracene-Treated Skin Carcinogenesis in Swiss Mice: A Comparison by Three-Compartment Model†¶

Photochemistry and Photobiology ◽

10.1562/0031-8655(2002)076<0081:ivpoaa>2.0.co;2 ◽

2002 ◽

Vol 76 (1) ◽

pp. 81 ◽

Cited By ~ 2

Author(s):

Parmeswaran Diagaradjane ◽

Sankaranarayanapillai Madhuri ◽

Prakasarao Aruna ◽

Pradeep Kumar Gupta ◽

Singaravelu Ganesan

Keyword(s):

Photodynamic Therapy ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Compartment Model ◽

Skin Carcinogenesis ◽

Swiss Mice ◽

Three Compartment Model ◽

In Vivo Pharmacokinetics

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Kinetics of protoporphyrin IX formation in rat oral mucosa and skin after application of 5-aminolevulinic acid and its methylester

Photochemistry and Photobiology ◽

10.1562/2004-04-02-ra-132 ◽

2004 ◽

Author(s):

Stefan Kristiansson ◽

Asta Juzeniene ◽

Petras Juzenas ◽

Vladimir Iani ◽

Lennart Löfgren ◽

...

Keyword(s):

Oral Mucosa ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Kinetics Of

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Chimeric Mouse With Humanized Liver Is an Appropriate Animal Model to Investigate Mode of Action for Porphyria-Mediated Hepatocytotoxicity

Toxicologic Pathology ◽

10.1177/01926233211027474 ◽

2021 ◽

pp. 019262332110274

Author(s):

Ayumi Eguchi ◽

Satoki Fukunaga ◽

Keiko Ogata ◽

Masahiko Kushida ◽

Hiroyuki Asano ◽

...

Keyword(s):

Experimental Model ◽

Mode Of Action ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Human Hepatocytes ◽

Chimeric Mouse ◽

Hepatocellular Injury ◽

Hepatocyte Necrosis ◽

Key Events

Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.

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