Combined trastuzumab and paclitaxel treatment better inhibits ErbB-2-mediated angiogenesis in breast carcinoma through a more effective inhibition of Akt than either treatment alone.

作者: Kristine S. Klos , Xiaoyan Zhou , Sangkyou Lee , Lianglin Zhang , Wentao Yang

DOI: 10.1002/CNCR.11656

关键词:

摘要: BACKGROUND Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is a humanized anti-ErbB-2 monoclonal antibody that has demonstrated antitumor function, especially in combination with other chemotherapies such as paclitaxel (Taxol; Bristol Myers-Squibb, Princeton, NJ), patients tumors overexpress ErbB-2. Because the repeated administration of low-dose chemotherapy, paclitaxel, endorsed an antiangiogenic effect vitro, and because trastuzumab was shown to inhibit angiogenesis tumor xenografts, authors investigated whether ErbB-2-mediated angiogenic responses would be inhibited more effectively by combined treatment plus trastuzumab. METHODS Tumor xenografts were established 37 severe immunodeficiency mice injecting mammary fat pad ErbB-2-overexpressing human breast carcinoma cells. Mice then treated immunoglobulin (IgG) control, trastuzumab, or paclitaxel. Tumorigenicity, lung metastasis, microvessel density (MVD) evaluated. Vascular endothelial growth factor (VEGF) secretion, cell migration after treatment, status phosphorylated Akt evaluated vitro determine mechanisms underlying inhibition ErbB-2-induced angiogenesis. RESULTS Mice exhibited significantly reduced mean volumes compared IgG control (419.5 mm3 vs. 786.6 mm3, P < 0.0001). had volume 543.9 574.9 mm3. Tumors from trastuzumab-plus-paclitaxel group also decreased MVD (30 ± 8 44 12 MVD, 0.05). The 35 7, similar paclitaxel-treated (35 9). Forty-four percent metastases lungs 50%, 63%, 75% groups, respectively. In cells secreted less VEGF than (185.9 pg/mL 233.2 pg/mL, 261.3 286.4 respectively). addition, conditioned media stimulated (31.0 47.0 cells, 39.2 67.5 Furthermore, phosphorylation contributed up-regulation treatments. CONCLUSIONS Combined either alone, which resulted pronounced tumoricidal effects. This may mediated via reduction Akt. Cancer 2003;98:1377–85. © 2003 American Society. DOI 10.1002/cncr.11656

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