Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model

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OBJECTIVE

Glioblastoma (GBM) is the most prevalent and the most aggressive of primary brain tumors. There is currently no effective treatment for this tumor. The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors' goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM.

METHODS

The 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors.

RESULTS

Glioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival.

CONCLUSIONS

Bypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy.

ABBREVIATIONS AMC = 7-amino-4-methylcoumarin; BBB = blood-brain barrier; GBM = glioblastoma; IT = intratumorally; IV = intravenously; MTT = monotetrazolium.

Article Information

Correspondence Thomas C. Chen, Departments of Neurosurgery and Pathology, University of Southern California, 2011 Zonal Ave., Los Angeles, CA 90033. email: thomas.chen@med.usc.edu.

INCLUDE WHEN CITING Published online April 14, 2017; DOI: 10.3171/2016.11.JNS161212.

Disclosures Dr. Chen discloses ownership in Cognos Therapeutics. This work was sponsored and funded by Pharmaco-kinesis, Inc.

© AANS, except where prohibited by US copyright law.

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Figures

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    Bortezomib is cytotoxic for human glioma cells in vitro. Glioma cells (U251, LN229, U87) were treated with bortezomib (0–25 nM) for 48 hours. Cell death was evaluated using the MTT assay. O.D. = optical density.

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    Bortezomib decreased subcutaneous tumor progression when administered IV. A: Glioma cells (U251) were implanted subcutaneously into athymic nu/nu mice. Fourteen days later, intravenous treatment was initiated: vehicle treatment (blue); bortezomib (36 μg total) (red). Subsequently animals were left untreated for 14 days. Bortezomib treatment significantly (p = 0.0145) decreased tumor growth rate. B: Glioma cells (U87) were implanted subcutaneously in athymic nude mice. Bortezomib was administered at a total dose of 36 μg by intravenous injection beginning on Day 30 postimplantation. Bortezomib significantly (p = 0.041) decreased tumor growth rate for subcutaneous tumors. Figure is available in color online only.

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    Bortezomib does not affect intracranial tumor progression when delivered systemically. Human glioma cells U251 (A) or U87 (B) were implanted intracranially; subsequently, mice were given bortezomib (36 μg total) (red) or vehicle (blue) IV. The brain tumor size was monitored by optical imaging weekly, and animal survival data were analyzed by Kaplan-Meier plot. There were no significant differences between bortezomib compared with vehicle saline control. Figure is available in color online only.

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    Bortezomib (BZM) administered IT is effective in increasing survival. Glioma cells (U251) were implanted intracranially. After 10 days, animals were treated IT with vehicle; bortezomib IV (36 μg total); bortezomib IT (low dose, 0.36 μg total); bortezomib IT (medium dose, 1.2 μg total); and bortezomib IT (high dose, 3.6 μg total). Local administration of bortezomib delayed tumor progression and significantly increased median survival time (from 23 to 34 and 37 days for medium and high doses, respectively). Statistical analysis showed the p values as follows: vehicle versus bortezomib IV (36 μg total), p = 0.9523 (not significant); bortezomib IV (3.6 μg) versus bortezomib IT (low dose, 0.36 μg total), p = 0.1104 (not significant); bortezomib IV (36 μg) versus bortezomib IT (medium dose, 1.2 μg total), p = 0.0005; and bortezomib IV (36 μg) versus bortezomib IT (high dose, 3.6 μg total), p = 0.0022. CED = convection-enhanced delivery. Figure is available in color online only.

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