A CXCR4 Antagonist CTCE-9908 Inhibits Primary Tumor Growth and Metastasis of Breast Cancer
A CXCR4 Antagonist CTCE-9908 Inhibits Primary Tumor Growth and Metastasis of Breast Cancer
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DOI：
10.1016/j.jss.2008.06.044
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发表时间：
2009-08-01
影响因子：
2.2
通讯作者：
Lucci, Anthony
中科院分区：
文献类型：
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作者：
Huang, Eugene H.;Singh, Balraj;Lucci, Anthony
背景CXCL 12/CXCR 4信号传导可能参与肿瘤生长和血管生成，以及癌细胞向骨和其他器官的归巢。我们的目的是确定用肽类拮抗剂抑制CXCR 4是否会减少乳腺癌的肿瘤生长和转移。我们使用了两种乳腺癌小鼠模型。在第一个模型中，将1 x 10（6）个转染荧光素酶的MDA-MB-231乳腺癌细胞植入腹股沟乳房脂肪垫中以产生原发性肿瘤。在第二个模型中，将1 × 10（5）个MDA-231-BSC 12细胞注射到左心室中以产生骨转移。CTCE-9908是竞争性结合CXCR 4的CXCL 12的肽类似物，用于测试抑制CXCR 4的效果。用CTCE-9908（25 mg/kg，皮下注射5 d/wk）处理来自每个小鼠模型的5只小鼠。每周使用生物发光成像对所有小鼠进行评估，以量化肿瘤负荷的相对体积。生物发光成像显示，用CTCE-9908治疗的小鼠具有比对照小鼠显著更少的原发性肿瘤负荷。在第5周和第6周，用CTCE-9908处理的小鼠的原发性肿瘤负荷分别减少7倍和5倍。与对照组相比，CTCE-9908治疗也显著抑制了转移率。在第5周和第6周，用CTCE-9908治疗的小鼠分别显示转移性肿瘤负荷减少9倍和减少20倍。CXCR 4拮抗剂治疗。CTCE-9908显著降低了乳腺癌小鼠模型中的转移以及原发性肿瘤生长。(C)2009 Elsevier Inc. All rights reserved.
Background. CXCL12/CXCR4 signaling may be involved in tumor growth and angiogenesis, and homing of cancer cells to bone and other organs. Our purpose was to determine whether inhibition of CXCR4 with a peptide-based antagonist would reduce tumor growth and metastasis of breast cancer.Methods. We used two mouse models of breast cancer. In the first model, 1 x 10(6) MDA-MB-231 breast cancer cells transfected with luciferase were implanted into the inguinal mammary fat pad to produce primary tumors. In the second model, 1 x 10(5) MDA-231-BSC12 cells were injected into the left cardiac ventricle to produce bone metastases. CTCE-9908, a peptide analog of CXCL12 that competitively binds to CXCR4, was used to test the effect of inhibiting CXCR4. Five mice from each mouse model were treated with CTCE-9908 (25 mg/kg, injected subcutaneously 5 d/wk). All mice were assessed weekly using bioluminescent imaging to quantify relative volumes of tumor burden.Results. Bioluminescencent imaging showed that the mice treated with CTCE-9908 had significantly less primary tumor burden than the control mice. At 5 and 6 wk, the mice treated with CTCE-9908 had a 7-fold reduction and 5-fold reduction in primary tumor burden, respectively. Treatment with CTCE-9908 also significantly inhibited the rate of metastases compared with the control group. At 5 and 6 wk, the mice treated with CTCE-9908 demonstrated a 9-fold reduction and 20-fold reduction in metastatic tumor burden, respectively.Conclusion. Treatment with the CXCR4 antagonist. CTCE-9908 significantly reduced metastasis as well as primary tumor growth in mouse models of breast cancer. (C) 2009 Elsevier Inc. All rights reserved.