Publications [#98472] of John H Sampson

Papers Published

1. PM Grossi, H Ochiai, GE Archer, RE McLendon, MR Zalutsky, AH Friedman, HS Friedman, DD Bigner, JH Sampson, Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer., Clinical cancer research : an official journal of the American Association for Cancer Research, United States, vol. 9 no. 15 (November, 2003), pp. 5514-20, ISSN 1078-0432
   (last updated on 2006/06/06)

   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.

   Keywords:
   Animals • Antibodies, Monoclonal • Antineoplastic Agents • Brain Neoplasms • Breast Neoplasms • Disease Models, Animal • Female • Infusions, Parenteral • Neoplasm Metastasis • Rats • Rats, Nude • Survival Analysis • administration & dosage • drug therapy* • pathology* • secondary* • therapeutic use*