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  • Title: Immunosuppressive and anticancer effect of a mammalian ribonuclease that targets high-affinity interleukin-2-receptors.
    Author: Yamamura T, Ueda M, Psarras K, Suwa T, Watanaabe Y, Kameyama N, Tanabe M, Imamura H, Kitajima M.
    Journal: Eur J Surg; 2002; 168(1):49-54. PubMed ID: 12022372.
    Abstract:
    OBJECTIVE: To target high-affinity interleukin (IL)-2 receptors involved in lymphocyte proliferation processes such as allograft rejection, autoimmune disorders, and certain haematological malignancies, using a minimally immunogenic mammalian-derived enzyme, bovine RNaseA, which becomes cytotoxic on entering cytoplasm. DESIGN: Laboratory study. SETTING: Teaching hospital, Japan. MATERIAL: Human lymphocytes isolated from healthy histoincompatible donors in mixed lymphocyte cultures or stimulated with phytohemagglutinin (PHA) to promote IL-2Ralpha expression. MJ, an HTLV-1-infected malignant T-cell line that overexpresses IL-2Ralpha, and the IL-2Ralpha-negative cell lines MOLT-4F and MT-1, were used as controls. INTERVENTIONS: Bovine RNaseA was chemically conjugated to 7G7B6, a monoclonal antibody to the alpha-chain of human IL-2 receptors, and several concentrations of the conjugates were added to the lymphocyte cultures. MAIN OUTCOME MEASURES: Inhibition of cell proliferation as a percentage of 3H-thymidine incorporation in 24 hours. RESULTS: 7G7B6-RNaseA dose-dependently inhibited cell proliferation in PHA-stimulated human lymphocytes at a 50% inhibitory concentration (IC50) of 2 x 10(-7) M. whereas RNase alone and RNase plus antibody had no inhibitory effect. 7G7B6-RNaseA also dose-dependently inhibited the human mixed lymphocyte reaction at an IC50 of 2 x 10(-6) M, whereas RNase alone did not. The conjugate also inhibited cell proliferation in MJ cells, a cell line that is infected with HTLV-I and overexpresses the high-affinity IL-2 receptor, at an IC50 of 5 x 10(-7) M. However the conjugate had no inhibitory effect on the IL-2 receptor non-expressing human T-cell lymphoblastic leukaemia cell lines MOLT-4F or MT-1. CONCLUSION: 7G7B6-RNaseA can inhibit cell proliferation in antigen- or mitogen-stimulated lymphocytes that overexpress high-affinity IL-2 receptors, and it may be safer than conventional chemotherapy or immunotoxins in the treatment of transplant rejection, certain lymphocytic malignancies, and other IL-2R-associated diseases, because it contains a mammalian cytotoxic enzyme.
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