title: 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.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: D Lynne
authors.initials: DL
authors.lastname: Smith
authors.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: SuTao
authors.initials: S
authors.lastname: Zhu
authors.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Wei
authors.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Fukumoto
authors.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Sanjai
authors.initials: S
authors.lastname: Sharma
authors.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Masood
authors.affiliation: University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004151:Dipeptides / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D004151:Dipeptides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C060736:thymogen; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma