Grossi Peter M, Ochiai Hidenobu, Archer Gary E, McLendon Roger E, Zalutsky Michael R, Friedman Allan H, Friedman Henry S, Bigner Darell D, Sampson John H
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Clin Cancer Res. 2003 Nov 15;9(15):5514-20.
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.
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.
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).
ICM of trastuzumab is safe and superior to systemic delivery as therapy for HER2-overexpressing intracerebral neoplasms in an athymic rat model.
单克隆抗体（MAb）曲妥珠单抗（赫赛汀）可有效治疗HER2过表达的脑外乳腺肿瘤。然而，将此类大分子治疗药物递送至脑内转移瘤受到脑血管紧密连接特性的限制。直接脑内微量注射（ICM）是一种绕过血脑屏障的技术，可使药物更大量地直接递送至脑内肿瘤。
将转染后过表达HER2的人乳腺癌细胞系MCF-7/HER2-18移植到无胸腺大鼠的大脑中。通过全身给药或ICM给予生理盐水、曲妥珠单抗或同型对照单克隆抗体，以评估毒性和疗效。
在任何研究条件下，均未发现与曲妥珠单抗相关的临床或组织学毒性。腹腔注射曲妥珠单抗（2mg/kg）导致中位生存期为26.5天，而通过ICM给予曲妥珠单抗（2mg/kg）可使中位生存期延长96%，至52天，9只大鼠中有2只存活超过120天（P = 0.009）。用同型对照单克隆抗体（16mg/kg）治疗导致中位生存期为21天，与用生理盐水进行ICM治疗的大鼠生存期（16天）无显著差异（P = 0.42）。用曲妥珠单抗（16mg/kg）进行ICM治疗导致中位生存期为45天，10只大鼠中有2只存活超过120天。这些结果分别比生理盐水和单克隆抗体对照组的中位生存期增加了181%和114%（P < 0.001）。
在无胸腺大鼠模型中，曲妥珠单抗的ICM作为HER2过表达脑内肿瘤的治疗方法是安全的，且优于全身给药。
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