Kondo Eisaku, Seto Masao, Yoshikawa Kazuhiro, Yoshino Tadashi
Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Mol Cancer Ther. 2004 Dec;3(12):1623-30.
Molecular targeting of hematopoietic malignancies has been generally hindered by technological obstacles to gene delivery in the neoplastic cells. The development of peptide delivery systems based on protein transduction domains has recently gained attention as a means of potentially overcoming these impediments. Here, we present a novel peptide transporter system that increases the efficiency of peptide delivery more than 10 times compared with the previous methods. The transporter, Wr-T, has an enlarged hydrophobic pocket consisting of triple tryptophan-rich domains fused with nine d-enantiomer polyarginines (r9) via Gly-Pro-Gly spacer, which serves to augment delivery of a cargo peptide. Wr-T-mediated transport of p16(INK4a) functional peptide dramatically inhibits growth of highly aggressive leukemia/lymphomas by up to 80% through restoration of p16 function. The Wr-T system thus represents a highly effective approach to cargo peptide delivery with the potential for substantially developing p16 peptide-based therapy for hematopoietic malignancies.
造血系统恶性肿瘤的分子靶向治疗通常受到肿瘤细胞中基因递送技术障碍的阻碍。基于蛋白质转导结构域的肽递送系统的发展最近作为一种潜在克服这些障碍的手段而受到关注。在此，我们展示了一种新型肽转运系统，与先前方法相比，其肽递送效率提高了10倍以上。该转运体Wr-T具有一个扩大的疏水口袋，由富含三个色氨酸的结构域组成，通过甘氨酸-脯氨酸-甘氨酸间隔区与九个d-对映体聚精氨酸（r9）融合，这有助于增强货物肽的递送。Wr-T介导的p16（INK4a）功能肽转运通过恢复p16功能，显著抑制高度侵袭性白血病/淋巴瘤的生长，抑制率高达80%。因此，Wr-T系统代表了一种高效的货物肽递送方法，具有为造血系统恶性肿瘤大幅开发基于p16肽的治疗方法的潜力。
