Temozolomide Delivered by Intracerebral Microinfusion is Safe and Efficacious Against Malignant Gliomas in Rats1
- Amy B. Heimberger,
- Gary E. Archer,
- Roger E. McLendon,
- Christine Hulette,
- Allan H. Friedman,
- Henry S. Friedman,
- Darell D. Bigner and
- John H. Sampson2
- Department of Surgery, Division of Neurosurgery [A. B. H., G. E. A., A. H. F., H. S. F., J. H. S.] and Department of Pathology [R. E. M., C. H., H. S. F., D. D. B., J. H. S.], Duke University Medical Center, Durham, North Carolina 27710
Abstract
Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for >100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by Grants CA11898 and NS20023 from the NIH, a grant from the American Association of Neurological Surgeons, and by a NIH Neuro-Oncology Research Fellowship.
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↵2 To whom requests for reprints should be addressed, at Division of Neurosurgery, Department of Surgery, Box 3807, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-9041; Fax: (919) 684-9045; E-mail: john.sampson{at}duke.edu
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↵3 The abbreviations used are: MG, malignant glioma; DPBS, Dulbecco’s PBS; ICM, intracerebral microinfusion.
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- Accepted July 13, 1900.
- Received February 25, 1900.
- Revision received July 12, 1900.
