Efficacy of Intracerebral Microinfusion of Trastuzumab in an Athymic Rat Model of Intracerebral Metastatic Breast Cancer
- Peter M. Grossi1,
- Hidenobu Ochiai1,
- Gary E. Archer1,
- Roger E. McLendon2,
- Michael R. Zalutsky23,
- Allan H. Friedman1,
- Henry S. Friedman1,
- Darell D. Bigner12 and
- John H. Sampson12
- 1Division of Neurosurgery, Department of Surgery, and
- 2Departments of Pathology and
- 3Radiology, Duke University Medical Center, Durham, North Carolina 27710
Abstract
Purpose: The monoclonal antibody (MAb) trastuzumab (Herceptin) effectively treats HER2-overexpressing extracerebral breast neoplasms. Delivery of such macromolecule therapeutic agents to intracerebral metastases, however, is limited by the tight junctions characteristic of the cerebral vasculature. Direct intracerebral microinfusion (ICM) is a technique that bypasses this blood-brain barrier and allows for a greater delivery of drugs directly into intracerebral tumors.
Experimental Design: A human breast cancer cell line transfected to overexpress HER2, MCF-7/HER2–18, was transplanted into the cerebrum of athymic rats. Saline, trastuzumab, or an isotype-matched control MAb was delivered systemically or by ICM to assess toxicity and efficacy.
Results: No clinical or histological toxicity related to trastuzumab was evident under any of the conditions studied. Delivery of trastuzumab (2 mg/kg) i.p. led to a median survival of 26.5 days, whereas treatment with trastuzumab (2 mg/kg) by ICM increased the median survival by 96% to 52 days, with two of nine rats surviving >120 days (P = 0.009). Treatment with an isotype-matched control MAb (16 mg/kg) resulted in a median survival of 21 days, which did not differ significantly from the survival of rats treated by ICM with saline (16 days; P = 0.42). Treatment by ICM with trastuzumab (16 mg/kg) led to a median survival of 45 days, with 2 of 10 rats surviving >120 days. These results represent 181% and 114% increases in median survival over the saline and MAb controls, respectively (P < 0.001).
Conclusion: ICM of trastuzumab is safe and superior to systemic delivery as therapy for HER2-overexpressing intracerebral neoplasms in an athymic rat model.
Footnotes
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Grant support: Stead Scholarship, Duke University School of Medicine (to P. M. G.), Sidney Kimmel Foundation for Cancer Research (to J. H. S.), and NIH (U19 CA52857-11, R01-CA097611, and 5K23-RR-16065-02; to J. H. S.). Drugs were received from Genentech, Inc. (South San Francisco, CA).
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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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Requests for reprints: John H. Sampson, MD, PhD, Division of Neurosurgery, 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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↵4 The abbreviations used are: MAb, monoclonal antibody; BBB, blood brain barrier; CNS, central nervous system; ICM, intracerebral microinfusion; HPF, high-powered field; CI, confidence interval.
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↵5 J. H. Sampson, G. Akabani, D. D. Bigner, R. E. Coleman, A. H. Friedman, H. S. Friedman, I. Pastan, J. Provenzale, and D. A. Reardon, unpublished results.
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- Accepted June 7, 1903.
- Received June 10, 1902.
- Revision received May 27, 1903.
