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2016 ; 6
(ä): 211
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Intracerebral Distribution of the Oncometabolite d-2-Hydroxyglutarate in Mice
Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for
Tumorigenesis
#MMPMID27781195
Pickard AJ
; Sohn AS
; Bartenstein TF
; He S
; Zhang Y
; Gallo JM
Front Oncol
2016[]; 6
(ä): 211
PMID27781195
show ga
The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has
generated significant efforts to understand the role of the mutated enzyme
product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well
as means to eliminate it. Glymphatic clearance was proposed as a pathway that
could be manipulated to accelerate D2HG clearance and dictated the study design
that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral
tumors that underwent two microdialysis - providing D2HG interstitial fluid
concentrations - sampling periods of awake and asleep (activate glymphatic
clearance) in a crossover manner. Glymphatic clearance was found not to have a
significant effect on D2HG brain tumor interstitial fluid concentrations that
were 126.9?±?74.8??M awake and 117.6?±?98.6??M asleep. These concentrations,
although low relative to total brain tumor concentrations of 6.8?±?3.6?mM, were
considered sufficient to be transported by interstitial fluid and taken up into
normal cells to cause deleterious effects. A model of D2HG CNS distribution
supported this contention and was further supported by in vitro studies that
showed D2HG could interfere with immune cell function. The study provides insight
into the compartmental distribution of D2HG in the brain, wherein the
interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and
contribute to tumorigenesis.