Tamamura Hirokazu, Fujisawa Miho, 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. 2004 Jul 2;569(1-3):99-104. doi: 10.1016/j.febslet.2004.05.056.
Several recent papers support the involvement of an interaction between stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor, chemokine receptor CXCR4, in memory T cell migration in the inflamed rheumatoid arthritis (RA) synovium. Analogs of the 14-mer peptide T140 were previously found to be specific CXCR4 antagonists that were characterized as not only HIV-entry inhibitors but also anti-cancer-metastatic agents. In this study, a T140 analog, 4F-benzoyl-TN14003, was proven to inhibit CXCL12-mediated migration of human Jurkat cells and mouse splenocyte in a dose-dependent manner in vitro (IC(50)=0.65 and 0.54 nM, respectively). Furthermore, slow release administration by subcutaneous injection (s.c.) of 4F-benzoyl-TN14003 using an Alzet osmotic pump significantly suppressed the delayed-type hypersensitivity response induced by sheep red blood cells in mice, and significantly ameliorated clinical severity in collagen-induced arthritis in mice. As such, T140 analogs might be attractive lead compounds for chemotherapy of RA.
最近的几篇论文支持基质细胞衍生因子-1（SDF-1/CXCL12）与其受体趋化因子受体CXCR4之间的相互作用参与了记忆T细胞在炎症性类风湿关节炎（RA）滑膜中的迁移。先前发现14聚体肽T140的类似物是特异性CXCR4拮抗剂，其不仅被表征为HIV进入抑制剂，还被表征为抗癌转移剂。在本研究中，一种T140类似物4F-苯甲酰基-TN14003在体外被证明以剂量依赖性方式抑制人Jurkat细胞和小鼠脾细胞的CXCL12介导的迁移（IC(50)分别为0.65和0.54 nM）。此外，使用Alzet渗透泵通过皮下注射（s.c.）缓慢释放4F-苯甲酰基-TN14003可显著抑制小鼠中由绵羊红细胞诱导的迟发型超敏反应，并显著改善小鼠胶原诱导性关节炎的临床严重程度。因此，T140类似物可能是RA化疗有吸引力的先导化合物。
