CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model
CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model
复制标题
DOI：
10.1002/ijc.25665
复制
发表时间：
2011-07-01
影响因子：
6.4
通讯作者：
Basik, Mark
中科院分区：
文献类型：
--
作者：
Hassan, Saima;Buchanan, Marguerite;Basik, Mark
CXCR 4是一种趋化因子受体，参与癌细胞归巢至靶向转移器官，其过表达其配体基质细胞衍生因子（SDF）-1。为了确定靶向CXCR 4对原发性肿瘤生长和转移的功效，我们使用CXCR 4的肽抑制剂CTCE-9908，其使用转基因乳腺癌小鼠模型以临床相关方法施用。我们首先在PyMT小鼠模型中进行CTCE-9908的给药实验，在8-16只小鼠的组中测试25、50和100 mg/kg相对于乱序肽。然后，我们将CTCE-9908与多西他赛或DC 101（一种抗VEGFR 2单克隆抗体）组合。我们发现，单独增加剂量的CTCE-9908减缓了肿瘤生长的速率，在用50 mg/kg的CTCE-9908治疗3.5周时，原发性肿瘤生长的抑制率为45%（p = 0.005）。还发现CTCE-9908使VEGF的表达水平降低42%（p = 0.01）。与多西他赛联合给药时，CTCE-9908使肿瘤体积减小38%（p = 0.02），这一效应大于多西他赛单药时观察到的效应。与单独的DC 101相比，CTCE-9908与DC 101组合也表现出增强的效果，原发性肿瘤体积减少37%（p = 0.01），远处转移减少75%（p = 0.009）。CTCE-9908与多西他赛或抗血管生成剂联合使用时，其抗肿瘤和抗转移作用显著增强，提示可能是治疗乳腺癌的新的有效组合治疗策略，其中包括靶向SDF-1/CXCR 4配体/受体对。
CXCR4 is a chemokine receptor implicated in the homing of cancer cells to target metastatic organs, which overexpress its ligand, stromal cell-derived factor (SDF)-1. To determine the efficacy of targeting CXCR4 on primary tumor growth and metastasis, we used a peptide inhibitor of CXCR4, CTCE-9908, that was administered in a clinically relevant approach using a transgenic breast cancer mouse model. We first performed a dosing experiment of CTCE-9908 in the PyMT mouse model, testing 25, 50 and 100 mg/kg versus the scrambled peptide in groups of 8-16 mice. We then combined CTCE-9908 with docetaxel or DC101 (an anti-VEGFR2 monoclonal antibody). We found that increasing doses of CTCE-9908 alone slowed the rate of tumor growth, with a 45% inhibition of primary tumor growth at 3.5 weeks of treatment with 50 mg/kg of CTCE-9908 (p = 0.005). Expression levels of VEGF were also found to be reduced by 42% with CTCE-9908 (p = 0.01). In combination with docetaxel, CTCE-9908 administration decreased tumor volume by 38% (p = 0.02), an effect that was greater than that observed with docetaxel alone. In combination with DC101, CTCE-9908 also demonstrated an enhanced effect compared to DC101 alone, with a 37% decrease in primary tumor volume (p = 0.01) and a 75% reduction in distant metastasis (p = 0.009). In combination with docetaxel or an anti-angiogenic agent, the anti-tumor and anti-metastatic effects of CTCE-9908 were markedly enhanced, suggesting potentially new effective combinatorial therapeutic strategies in the treatment of breast cancer, which include targeting the SDF-1/CXCR4 ligand/receptor pair.