TY - JOUR
T1 - Efficacy of Intracerebral Microinfusion of Trastuzumab in an Athymic Rat Model of Intracerebral Metastatic Breast Cancer
AU - Grossi, Peter M.
AU - Ochiai, Hidenobu
AU - Archer, Gary E.
AU - McLendon, Roger E.
AU - Zalutsky, Michael R.
AU - Friedman, Allan H.
AU - Friedman, Henry S.
AU - Bigner, Darell D.
AU - Sampson, John H.
PY - 2003/11/15
Y1 - 2003/11/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/0344758982
M3 - Article
C2 - 14654531
AN - SCOPUS:0344758982
SN - 1078-0432
VL - 9
SP - 5514
EP - 5520
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -