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Efficacy of intracerebral microinfusion of trastuzumab in an
athymic rat model of intracerebral metastatic breast cancer
Grossi PM, Ochiai H, Archer GE, McLendon RE, Zalutsky MR, Friedman AH,
Friedman HS, Bigner DD, Sampson JH
Division of Neurosurgery, Department of Surgery, Duke University Medical Center,
Durham, North Carolina 27710, USA.
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.
PMID: 14654531 [PubMed - indexed for MEDLINE]
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