Apr 17, 2018

Modeling the diffusion of D-2-hydroxyglutarate from IDH1 mutant gliomas in the central nervous system

Neuro-oncology
Andreas LinningerCraig Horbinski

Abstract

Among diffusely infiltrative gliomas in adults, 20%-30% contain a point mutation in isocitrate dehydrogenase 1 (IDH1mut), which increases production of D-2-hydroxyglutarate (D2HG). This is so efficient that D2HG often reaches 30 mM within IDH1mut gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1mut glioma patients, the exposure of nonneoplastic cells within and surrounding an IDH1mut glioma to D2HG is unknown and difficult to measure directly. Conditioned medium from patient-derived wild type IDH1 (IDH1wt) and IDH1mut glioma cells was analyzed for D2HG by liquid chromatography-mass spectrometry (LC-MS). Mathematical models of D2HG release and diffusion around an IDH1mut glioma were independently generated based on fluid dynamics within the brain and on previously reported intratumoral and cerebrospinal D2HG concentrations. LC-MS analysis indicates that patient-derived IDH1mut glioma cells release 3.7-97.0 pg D2HG per cell per week. Extrapolating this to an average-sized tumor (30 mL glioma volume and 1 × 108 cells/mL tumor), the rate of D2HG release by an IDH1mut glioma (SA) is estimated at 3.2-83.0 × 10-12 mol/mL/sec. Mathematical models estimate an SA of 2.9-12.9 × 10-12 mol/...Continue Reading

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Citations

Mentioned in this Paper

Health Center
Sulfanilamide
Central Nervous System
alpha-hydroxyglutarate, disodium salt
Intratumoral
Nevus
Cancer Microenvironment
Extracellular
Talpidae
Culture Media, Conditioned

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