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¹ Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; ² Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan; and ³ Second Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Requests for reprints: Eisaku Kondo, Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558 Japan. Phone: 81-86-235-7151; Fax: 81-86-235-7156. E-mail: ekondo{at}md.okayama-u.ac.jp

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.

Key Words: peptide therapy • transporter • p16 • leukemia/lymphoma • inhibition

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Received 6/21/04; revised 9/ 8/04; accepted 9/28/04.