title: Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas.
abstract: Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has become the main treatment modality in malignant gliomas. However unlike glioblastomas, there are inconsistent result about fluorescence status in WHO grade III gliomas. Here, we show that mutational status of IDH1 is linked to 5-ALA fluorescence. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) IDH1, we demonstrated a lag in 5-ALA metabolism and accumulation of protoporphyrin IX (PpIX) in U87MG-IDH1R132Hcells. Next, we used liquid chromatography-mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes caused by 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. High levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporarily enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. In conclusion, we have discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Low levels of NADPH in tumors with mutated IDH1 is responsible for the enhanced fluorescence.
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Ja Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Radiology, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Natural Product Research Institute, Seoul National University, Sillim-dong, Gwanak-gu, Seoul, Korea.
authors.forename: Wen Jun
authors.initials: WJ
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Korea.
authors.forename: Sung Kwon
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.|Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Radiology, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Hyeonjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Radiology, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Seung Hong
authors.initials: SH
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Natural Product Research Institute, Seoul National University, Sillim-dong, Gwanak-gu, Seoul, Korea.
authors.forename: Sunghyouk
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
mesh_terms: D000622:Aminolevulinic Acid / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*
chemical_list: D000622:Aminolevulinic Acid; D007521:Isocitrate Dehydrogenase
keywords: 5-ALA; IDH1; NADPH; brain tumors; fluorescence; glioma; oncology