Tamamura Hirokazu, Hori Akira, Kanzaki Naoyuki, Hiramatsu Kenichi, Mizumoto Makiko, Nakashima Hideki, Yamamoto Naoki, Otaka Akira, Fujii Nobutaka
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
FEBS Lett. 2003 Aug 28;550(1-3):79-83. doi: 10.1016/s0014-5793(03)00824-x.
A chemokine receptor, CXCR4, and its endogenous ligand, stromal cell-derived factor-1 (SDF-1), have been recognized to be involved in the metastasis of several types of cancers. T140 analogs are peptidic CXCR4 antagonists composed of 14 amino acid residues that were previously developed as anti-HIV agents having inhibitory activity against HIV-entry through its co-receptor, CXCR4. Herein, we report that these compounds effectively inhibited SDF-1-induced migration of human breast cancer cells (MDA-MB-231), human leukemia T cells (Sup-T1) and human umbilical vein endothelial cells at concentrations of 10-100 nM in vitro. Furthermore, slow release administration by subcutaneous injection using an Alzet osmotic pump of a potent and bio-stable T140 analog, 4F-benzoyl-TN14003, gave a partial, but statistically significant (P</=0.05 (t-test)) reduction in pulmonary metastasis of MDA-MB-231 in SCID mice, even though no attempt was made to inhibit other important targets such as CCR7. These results suggest that T140 analogs have potential use for cancer therapy, and that small molecular CXCR4 antagonists could potentially replace neutralizing antibodies as anti-metastatic agents for breast cancer.
趋化因子受体CXCR4及其内源性配体基质细胞衍生因子-1（SDF-1）已被证实与多种癌症的转移有关。T140类似物是由14个氨基酸残基组成的肽类CXCR4拮抗剂，其最初是作为抗HIV药物开发的，通过其共受体CXCR4对HIV进入具有抑制活性。在此，我们报告这些化合物在体外浓度为10-100 nM时能有效抑制SDF-1诱导的人乳腺癌细胞（MDA-MB-231）、人白血病T细胞（Sup-T1）和人脐静脉内皮细胞的迁移。此外，使用Alzet渗透泵通过皮下注射缓慢释放一种强效且生物稳定的T140类似物4F-苯甲酰基-TN14003，在SCID小鼠中使MDA-MB-231的肺转移有部分但具有统计学意义（P≤0.05（t检验））的降低，尽管未尝试抑制其他重要靶点如CCR7。这些结果表明T140类似物在癌症治疗中有潜在用途，并且小分子CXCR4拮抗剂有可能替代中和抗体作为乳腺癌的抗转移药物。
