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Noninvasive Bioluminescence Imaging of Luciferase Expressing Intracranial U87 Xenografts: Correlation with Magnetic Resonance Imaging Determined Tumor Volume and Longitudinal Use in Assessing Tumor Growth and Antiangiogenic Treatment Effect

Szentirmai, Oszkar M.D.; Baker, Cheryl H. Ph.D.; Lin, Ning B.S.; Szucs, Szofia M.D.; Takahashi, Masaya Ph.D.; Kiryu, Shigeru Ph.D.; Kung, Andrew L. M.D., Ph.D.; Mulligan, Richard C. Ph.D.; Carter, Bob S. M.D., Ph.D.

doi: 10.1227/01.NEU.0000195114.24819.4F
Experimental Studies: Imaging: Molecular & Cellular Biology: Tumor

OBJECTIVE: Outcome studies in rodent tumor models rely on both histological and noninvasive study end points. Intracranial models require special tools to observe tumor growth over time noninvasively, such as magnetic resonance imaging (MRI), computed tomographic scanning, or cranial window techniques. These techniques share disadvantages in terms of cost, technical expertise required, and overall animal throughput for analysis. In this report, we sought to validate the use of the relatively newer technique of bioluminescence imaging (BLI) of intracranial glioblastoma xenograft growth by comparing it with gadolinium-enhanced MRI.

METHODS: U87MG glioma cell lines genetically engineered to express the firefly luciferase gene were stereotactically injected into nude mice in the left frontal lobe. Weekly BLI and MRI were performed after the inoculation of tumor cells. For BLI, tumor growth was assessed as the peak BLI after systemic injection of luciferin substrate. MRI-based growth curves were created by three-dimensional volumetric reconstruction of axial gadolinium-enhanced MRI data covering the whole brain. In a separate experiment, mice were treated with adenoviruses encoding antiangiogenic soluble vascular endothelial growth factor receptors, and treatment effect was monitored by BLI.

RESULTS: Untreated tumor growth was readily detected and observed over time by serial BLI measurements. Furthermore, tumor-derived light emission was highly correlated with volume of tumor as assessed by MRI. Furthermore, the tested antiangiogenic treatment effect was readily detected using this technique, suggesting the power of the technique for sensitive monitoring of novel therapeutics.

CONCLUSION: BLI offers a simple and rapid technique for assessing intracranial glioblastoma growth in rodent models noninvasively, which correlates well with MRI. The speed of the BLI technique can increase experimental throughput, allows for targeted histological analysis in animals showing the greatest treatment effects, and provides new insights into the kinetics of intracranial tumor growth in the setting of different treatments.

Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Szentirmai, Lin, Szucs, Carter)

Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas (Baker)

Department of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts (Takahashi, Kiryu)

Department of Pediatric Oncology, Dana Farber Cancer Institute, Children's Hospital and Harvard Medical School, Boston, Massachusetts (Kung)

Department of Genetics, Harvard Medical School and Children's Hospital, Boston, Massachusetts (Mulligan)

Reprint requests: Bob S. Carter, M.D., Ph.D., Neurosurgical Service, Yawkey Building, Room 9026, Massachusetts General Hospital, Boston, MA 02114. Email: bcarter@partners.org

Received, March 16, 2005.

Accepted, September 2, 2005.

Copyright © by the Congress of Neurological Surgeons