INVESTIGATION OF THE BIOLOGICAL EFFECTS OF ANTI-CELL ADHESIVE SYNTHETIC PEPTIDES THAT INHIBIT EXPERIMENTAL METASTASIS OF B16-F10 MURINE MELANOMA-CELLS
INVESTIGATION OF THE BIOLOGICAL EFFECTS OF ANTI-CELL ADHESIVE SYNTHETIC PEPTIDES THAT INHIBIT EXPERIMENTAL METASTASIS OF B16-F10 MURINE MELANOMA-CELLS
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DOI：
10.1172/jci113384
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发表时间：
1988-03-01
影响因子：
15.9
通讯作者：
OLDEN, K
中科院分区：
文献类型：
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作者：
HUMPHRIES, MJ;YAMADA, KM;OLDEN, K
抗细胞粘附五肽Gly-Arg-Gly-Asp-Ser（GRGDS）阻断B16-F10小鼠黑色素瘤细胞的实验性转移。在这份报告中，我们表明，肽治疗大大延长了静脉注射B16-F10细胞的小鼠的存活时间（8/8对0/8小鼠在150天存活），从而证明了GRGDS治疗在保护免受转移性定植方面的潜在功效。我们还通过测试一系列相关同源物对实验性转移的影响来检查GRGDS活性的特异性。这些肽的相对抑制活性的总体概况与其先前建立的体外破坏粘附的能力密切匹配。用放射性标记的B16-F10细胞进行的肺滞留研究显示，在与活性肽GRDGS共注射后0-6小时，肺细胞损失速率加快。GRGDS的这种早期效应与其短循环半衰期一致，这是喜欢8分钟。总之，这些结果表明，肽介导的抑制肺定植是由于干扰B16-F10细胞粘附到靶器官的结构。检查了肿瘤细胞-血细胞相互作用中可能的肽干扰，以评估（a）肽治疗的可能的生物学副作用和（B）这种相互作用是否可能是GRGDS介导的肺定植抑制的替代机制。当将GRGDS与B16-F10细胞共注射到经乙酰水杨酸处理的血小板功能受损的小鼠或经抗血小板血清处理的血小板减少症小鼠中时，发现GRGDS保留完全抑制活性（76-93%的集落形成抑制）。这些数据表明，血小板参与肽的作用是最小的。类似地，还发现GRGDS是自然杀伤（NK）细胞缺陷的米色小鼠中实验转移的有效抑制剂（86%抑制），从而排除了GRGDS人为增强NK细胞活性的可能性。我们得出结论，作为这些研究的结果，细胞结合纤连蛋白肽是延长生存期的实验性转移的特异性抑制剂，它们似乎通过阻断B16-F10细胞与靶器官结构的粘附来发挥作用，并且它们似乎不会通过对某些转移相关的血细胞功能的副作用来发挥作用。在未来，纤连蛋白肽的衍生物可能是潜在的有用的预防剂干扰转移的过程。
The experimental metastaiss of B16-F10 murine melanoma cells is blocked by the anti-cell adhesive pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) derived from the central cell-binding domain of fibronectin. In this report, we show that peptide treatment substantially extends the survival time for mice injected intravenously with B16-F10 cells (8/8 vs. 0/8 mice alive at 150 d), thereby demonstrating the potential efficacy of GRGDS treatment in protection against metastatic colonization. We have also examined the specificity of GRGDS activity by testing a series of related homologues for their effects on experimental metastasis. The overall profile of the relative inhibitory activities of these peptides closely matched their previously established capacity to disrupt adhesion in vitro. Lung retention studies with radiolabeled B16-F10 cells revealed an accelerated rate of cell loss from the lung 0-6 h after coinjection with the active peptide GRDGS. This early effect of GRGDS was consistent with its short circulatory half-life, which was fond to be 8 min. Taken together, these results suggest that peptide-mediated inhibition of pulmonary colonization is due to interference with B16-F10 cell adhesion to structures in the target organ. Possible peptide interference in tumor cell-blood cell interactions was examined in order to assess (a) possible biological side-effects of peptide treatment and (b) whether such interactions might be an alternative mechanism for GRGDS-mediated inhibition of pulmonary colonization. GRGDS was found to retain fully inhibitory activity when coinjected with B16-F10 cells into mice in which platelet function was impaired by acetylsalicylic acid treatment or into thrombocytopenic mice treated with antiplatelet serum (76-93% inhibition of colony formation). These data suggest that platelet involvement in the effects of the peptide is minimal. Similarly, GRGDS was also found to be a potent inhibitor of experimental metastasis in natural killer (NK) cell-deficient beige mice (86% inhibition), thereby discounting the possibility that GRGDS artifactually enhanced NK cell activity. We conclude as a result of these studies that cell-binding fibronectin peptides are specific inhibitors of experimental metastasis that prolong survival, that they appear to function by blocking the adhesion of B16-F10 cells to structures in the target organ, and that they do not appear to act through side effects on certain metastasis-related blood cell functions. In the future, derivatives of fibronectin peptides may be potentially useful prophylactic agents for interfering with the process of metastasis.