Bioluminescence monitoring of intracranial glioblastoma xenograft: response to primary and salvage temozolomide therapy

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  • 1 Neuroscience Graduate Program and
  • 2 Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota; and
  • 3 Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco
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Object

Bioluminescence imaging (BLI) offers a rapid and accurate means for longitudinal study of tumor cell growth and response to therapy in rodent models. Because this technology has only recently come into use in the field of small animal imaging, applications in this area have been limited. In the current study we have applied BLI to the analysis of clinically relevant issues involving use of the DNA methylating agent temozolomide (TMZ) in a mouse model.

Methods

An invasive glioblastoma multiforme xenograft was modified for BLI via transduction with a luciferase-encoding lentivirus. Supratentorial tumors were established in athymic nude mice that were subsequently assigned randomly to control and TMZ treatment groups, and the extent of intracranial tumor was monitored using BLI.

Results

In an experiment designed to compare the extent of antitumor effect between a single high-dose TMZ treatment and a protracted low-dose TMZ regimen, BLI revealed the protracted regimen as having superior antitumor effect, and this interpretation was consistent with results from a survival comparison between the two TMZ treatment groups. In a second experiment designed to assess the utility of BLI for testing therapies against recurrent glioblastoma multiforme, mice with intracranial tumors were retreated with TMZ at a time when BLI monitoring revealed tumor regrowth following initial TMZ treatment, and retreatment was successful in providing additional survival benefit.

Conclusion

The results of these experiments indicate that BLI monitoring can be used as a surrogate for predicting survival benefit from TMZ treatment, permits early determination of relative survival benefit associated with distinct TMZ therapeutic regimens, and offers a means of investigating secondary/salvage therapy efficacy following tumor regrowth from initial therapy.

Abbreviations used in this paper:BLI = bioluminescence imaging; GBM = glioblastoma multiforme; MGMT = O6-methylguanine DNA methyltransferase; PBS = phosphate-buffered saline; TMZ = temozolomide.

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Contributor Notes

Address reprint requests to: C. David James, Ph.D., Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143. email: david.james@ucsf.edu.
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