Malignant glioma: MR imaging by using 5-aminolevulinic acid in an animal model.
OBJECTIVE
To evaluate the use of 5-aminolevulinic acid (5-ALA) for the noninvasive detection of malignant gliomas by using in vivo magnetic resonance (MR) imaging in a mouse brain tumor model.


METHODS
The experiments were animal care committee approved. U-87 glioblastoma cells were exposed to 5-ALA (500 µmol/L) for 6 hours, cells were harvested, and intracellular concentrations of iron, heme, protoporphyrin IX, and ferrochelatase were measured (six in each group). BALB/c nude mice (n = 10) were inoculated with U-87 glioma cells to produce orthotopic brain tumors. T2-weighted imaging was performed 3 weeks after inoculation, and T2* maps were created with a 7-T MR imager before and 24 hours after oral administration of 5-ALA (0.1 mg/g of body weight; n = 6) or normal saline (n = 4). Intratumoral iron concentrations were measured with laser ablation inductively coupled plasma mass spectrometry. For in vitro experiments, differences in the measured data were assessed by using the Mann-Whitney U test with Bonferroni correction. For the in vivo studies, differences in T2* values and iron concentrations of the tumors in the 5-ALA and control groups were assessed by using the Mann-Whitney U test.


RESULTS
The intracellular concentration of heme and iron was increased at both 24 and 48 hours after 5-ALA exposure (P = .004). 5-ALA promoted expression of ferrochelatase in glioblastoma cells at both 24 and 48 hours after 5-ALA exposure compared with that at 1 hour (P = .004). In vivo MR imaging revealed a lower median T2* value in glioblastomas treated with 5-ALA compared with those in control mice (14.0 msec [interquartile range, 13.0-14.5 msec] vs 21.9 msec [interquartile range, 19.6-23.2 msec]; P = .011), and laser ablation inductively coupled plasma mass spectrometry revealed that iron concentrations were increased in glioblastomas from the 5-ALA group.


CONCLUSIONS
Administration of 5-ALA increased the intracellular iron concentration of glioblastomas by promoting the synthesis of heme, which is the metabolite of 5-ALA. Because intracellular iron can be detected at MR imaging, 5-ALA may aid in the identification of high-grade foci in gliomas.
From the Departments of Radiology (H.R.C., D.H.K., W.K.M., M.H.H., S.H.C.), Radiation Applied Life Science (H.R.C.), and Neurosurgery (C.K.P.), Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, Korea; Research Institute, National Cancer Center, Gyeonggi-do, Korea (D.K.); Department of Chemistry and Forensic Science, University of Technology, Sydney, Australia (P.D., D.B., D.H.); and Center for Nanoparticle Research, Institute for Basic Science (S.H.C.), and School of Chemical and Biological Engineering (S.H.C.), Seoul National University, Seoul, Korea.
Hye Rim
HR
Cho
Dong Hyun
DH
Kim
Daehong
D
Kim
Philip
P
Doble
David
D
Bishop
Dominic
D
Hare
Chul-Kee
CK
Park
Woo Kyung
WK
Moon
Moon Hee
MH
Han
Seung Hong
SH
Choi
D000622:Aminolevulinic Acid / Q000493:pharmacokinetics; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D003287:Contrast Media; D000622:Aminolevulinic Acid; D007501:Iron