1H MR spectroscopic imaging of phospholipase-mediated membrane lipid release in apoptotic rat glioma in vivo.
The purpose of the current study was to determine regional spatiotemporal differences and to gain insight on the mechanisms responsible for lipid accumulation during apoptotic cell death using in vivo MR spectroscopic imaging in combination with histology and biochemical membrane lipid analyses. Rats bearing BT4C gliomas were treated with ganciclovir (GCV) for 14 days, and combined in vivo quantitative MR spectroscopic imaging (MRSI) of gliomas with histology and a biochemical analysis of major cell membrane constituents. By using 1H MRSI in vivo in combination with histology, we were able to demonstrate previously unattainable regional lipid concentration differences in tumors during GCV-induced apoptosis, with 5-microL tissue volume resolution. Our results also show that, during treatment, phospholipase A2 (PLA2) expression is significantly elevated by 37+/-13% (P<0.05) and tumor cell membranes loose a significant proportion of unsaturated fatty acyl moieties (56+/-6 mmol/kg, P<0.05). These changes are reflected in both histology and significant MR-visible lipid accumulation, demonstrating that phospholipid hydrolysis in tissue undergoing apoptosis can be imaged with MRSI. Our work demonstrates the versatility of 1H MRSI in studying apoptosis in vivo, which is likely to pave way for the use of MRSI in both experimental and clinical anticancer trials.
Department of Biomedical NMR, A.I. Virtanen Institute, University of Kuopio, and Gene Therapy Unit, Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland. tliimata@cmrr.umn.edu
Timo J
TJ
Liimatainen
Arja T
AT
Erkkilä
Piia
P
Valonen
Helvi
H
Vidgren
Merja
M
Lakso
Garry
G
Wong
Olli H J
OH
Gröhn
Seppo
S
Ylä-Herttuala
Juhana M
JM
Hakumäki
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015774:Ganciclovir / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D050356:Lipid Metabolism / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008563:Membrane Lipids / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism; D051381:Rats
D008563:Membrane Lipids; D054467:Phospholipases A2; D015774:Ganciclovir