Natural killer cell cytolytic activity is necessary for in vivo antitumor activity of the dipeptide L-glutamyl-L-tryptophan.

Abstract

A dipeptide, L-glutamyl L-tryptophan (L-glu-L-trp), was identified in a screen for immunomodulators in the soluble fraction of the thymus. L-glu-L-trp inhibits tumor growth in mice without showing direct cellular toxicity in a variety of human tumor cell lines. L-glu-L-trp antitumor activity in vivo requires the presence of natural killer (NK) cells. Defective trafficking of cytoplasmic granules caused by the Lyst mutation also resulted in loss of antitumor activity of the dipeptide. The effect of L-glu-L-trp on tumor growth in mice with targeted gene mutations demonstrated the absolute requirement for perforin for antitumor activity. The requirement of 2 major modulators of NK cell activity, gamma interferon (IFNgamma) and interleukin (IL)-12, were also tested. L-glu-L-trp had full antitumor activity in IFNgamma knockout mice, but had significantly diminished activity in IL-12 knockout mice. These data show that L-glu-L-trp antitumor activity in mice is dependent on cytolytic cell activity of NK or NKT cells. L-glu-L-trp in vivo regulates NK cell function independent of IFNgamma but partly dependent on IL-12.

• Authors: D Lynne Smith, Jie Cai, SuTao Zhu, Wen Wei, Jon Fukumoto, Sanjai Sharma, Rizwan Masood, Parkash S Gill
• Journal: International journal of cancer (Int J Cancer) Vol. 106 Issue 4 Pg. 528-533 (Sep 10 2003) ISSN: 0020-7136 [Print] United States
• PMID: 12845648 (Publication Type: Journal Article)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Angiogenesis Inhibitors
• Dipeptides
• Membrane Glycoproteins
• Pore Forming Cytotoxic Proteins
• thymogen
• Perforin
• Interleukin-12
• Interferon-gamma

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Cell Division (drug effects)
• Cytoplasmic Granules (metabolism)
• Cytotoxicity, Immunologic
• Dipeptides (therapeutic use)
• Flow Cytometry
• Humans
• Interferon-gamma (deficiency, genetics, metabolism)
• Interleukin-12 (deficiency, genetics, metabolism)
• Killer Cells, Natural (physiology)
• Lung Neoplasms (drug therapy, immunology, secondary)
• Melanoma (drug therapy, immunology, secondary)
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasms, Experimental
• Perforin
• Pore Forming Cytotoxic Proteins
• T-Lymphocytes (physiology)
• Tumor Cells, Cultured