PHARMACOLOGY DIVISION

5.PHARMACOLOGY DIVISION

    The research program in the Pharmacology Division focuses on the discovery of new approaches for cancer treatments that can be clinically applied. The basis of this research is a fundamental investigation of the anti-tumor mechanisms of immune effector cells and target based drugs. The more translational research projects include development of the most effective immunotherapy and appropriate schedules for different types of drugs in combination chemotherapy.
Anti-tumor Immunity of Immunocompetent Cells and Allogeneic Transplantation Immunotherapy

    A U1B3.3 monoclonal antibody was established by immunizing a rat with the tMK-2U lymphoma cell line, derived from athymic nude mice. A precursor of NK1.1⁺ cytotoxic T cells generated by interleukin-2 was recognized by this antibody ⁽⁹³⁾. The therapeutic potential of a reduced-intensity preparative regimen for allogeneic transplantation with cladribine, busulfan, and antithymocyte globulin against advanced/refractory acute leukemia/lymphoma was reported ⁽⁹⁴⁾. The role of prostaglandin E₂ (PGE₂ ) in the function of dendritic cells, T-cell polarization and expression of chemokine receptor was evaluated in human cells ⁽⁹⁵⁾.
Immune Surveillance and Tumor Immunity at the Lipid Microdomains

    Structural analyses of lipid antigens are important to understand the molecular mechanisms and the pathogenesis of immune abnormalities including autoimmune diseases and tumor immunity. The TC-CCC was developed not only to separate but also to analyze the hydrophobic-molecular interaction ⁽⁹⁶⁾ for the analysis of the structure-activity relationship of glycolipids.
A Xenograft Derived from an Inflammatory Breast Cancer Showing Vasculogenic Mimicry

    The hemodynamics of our unique human xenograft named WIBC-9 established from an inflammatory breast cancer showing vasculogenic mimicry were analysed using time-course dynamic micromagnetic resonance angiography ⁽⁹⁷⁾. The rapid blood flow and perfusion of macromolecules in this xenograft WIBC-9 were evaluated in mice using 3D-micro-MR angiography using a novel macromolecular MR contrast agent [G6-(1B4M-Gd)(256)] ⁽⁹⁸⁾. The efficacy of growth inhibition of WIBC-9 with soluble Flt-1 (sFlt-1) and soluble Tie2 (sTie2) correlated with the number of tumor-infiltrating endothelial precursor cells ⁽⁹⁹⁾). 7.9% (26 specimens) of the 331 surgically resected breast cancer specimens exhibited evidence of vasculogenic mimicry and showed poor prognosis ⁽¹⁰⁰⁾. Postnatal vasculogenesis in breast-cancer-bearing mice was shown by an elevated endothelial precursor cell population from bone marrow, peripheral blood and tumour-infiltrating cells from these mice ⁽¹⁰¹⁾.
Biological and Biochemical Pharmacology

    The combination effects of cisplatin and target-based drugs were demonstrated ⁽¹⁰²⁾. The mechanisms for the combination effects of cytotoxic drugs ⁽¹⁰³⁾ and cytokines or radiotherapy were analyzed ^(104,¹⁰⁵⁾. Antitumor activities of target-based drugs were evaluated in vitro and in vivo ⁽¹⁰⁶⁾. Increased expression levels of oncoprotein 18, osteopontin ⁽¹⁰⁷⁾, and ganglioside-related genes ⁽¹⁰⁸⁾ in lung tumors correlated with cellular sensitivity to chemotherapy and target-based therapy in lung cancer. To demonstrate proof of the principle and to establish useful surrogate markers for tumor response, molecular correlative studies were conducted for target-based drugs. In vitro thermo-and thermochemosensitivity of retinoblastoma cells from surgical specimens were reported ⁽¹⁰⁹⁾.




5.PHARMACOLOGY DIVISION



	The research program in the Pharmacology Division focuses on the discovery of new approaches for cancer treatments that can be clinically applied. The basis of this research is a fundamental investigation of the anti-tumor mechanisms of immune effector cells and target based drugs. The more translational research projects include development of the most effective immunotherapy and appropriate schedules for different types of drugs in combination chemotherapy. Anti-tumor Immunity of Immunocompetent Cells and Allogeneic Transplantation Immunotherapy A U1B3.3 monoclonal antibody was established by immunizing a rat with the tMK-2U lymphoma cell line, derived from athymic nude mice. A precursor of NK1.1⁺ cytotoxic T cells generated by interleukin-2 was recognized by this antibody ⁽⁹³⁾. The therapeutic potential of a reduced-intensity preparative regimen for allogeneic transplantation with cladribine, busulfan, and antithymocyte globulin against advanced/refractory acute leukemia/lymphoma was reported ⁽⁹⁴⁾. The role of prostaglandin E₂ (PGE₂ ) in the function of dendritic cells, T-cell polarization and expression of chemokine receptor was evaluated in human cells ⁽⁹⁵⁾. Immune Surveillance and Tumor Immunity at the Lipid Microdomains Structural analyses of lipid antigens are important to understand the molecular mechanisms and the pathogenesis of immune abnormalities including autoimmune diseases and tumor immunity. The TC-CCC was developed not only to separate but also to analyze the hydrophobic-molecular interaction ⁽⁹⁶⁾ for the analysis of the structure-activity relationship of glycolipids. A Xenograft Derived from an Inflammatory Breast Cancer Showing Vasculogenic Mimicry The hemodynamics of our unique human xenograft named WIBC-9 established from an inflammatory breast cancer showing vasculogenic mimicry were analysed using time-course dynamic micromagnetic resonance angiography ⁽⁹⁷⁾. The rapid blood flow and perfusion of macromolecules in this xenograft WIBC-9 were evaluated in mice using 3D-micro-MR angiography using a novel macromolecular MR contrast agent [G6-(1B4M-Gd)(256)] ⁽⁹⁸⁾. The efficacy of growth inhibition of WIBC-9 with soluble Flt-1 (sFlt-1) and soluble Tie2 (sTie2) correlated with the number of tumor-infiltrating endothelial precursor cells ⁽⁹⁹⁾). 7.9% (26 specimens) of the 331 surgically resected breast cancer specimens exhibited evidence of vasculogenic mimicry and showed poor prognosis ⁽¹⁰⁰⁾. Postnatal vasculogenesis in breast-cancer-bearing mice was shown by an elevated endothelial precursor cell population from bone marrow, peripheral blood and tumour-infiltrating cells from these mice ⁽¹⁰¹⁾. Biological and Biochemical Pharmacology The combination effects of cisplatin and target-based drugs were demonstrated ⁽¹⁰²⁾. The mechanisms for the combination effects of cytotoxic drugs ⁽¹⁰³⁾ and cytokines or radiotherapy were analyzed ^(104,¹⁰⁵⁾. Antitumor activities of target-based drugs were evaluated in vitro and in vivo ⁽¹⁰⁶⁾. Increased expression levels of oncoprotein 18, osteopontin ⁽¹⁰⁷⁾, and ganglioside-related genes ⁽¹⁰⁸⁾ in lung tumors correlated with cellular sensitivity to chemotherapy and target-based therapy in lung cancer. To demonstrate proof of the principle and to establish useful surrogate markers for tumor response, molecular correlative studies were conducted for target-based drugs. In vitro thermo-and thermochemosensitivity of retinoblastoma cells from surgical specimens were reported ⁽¹⁰⁹⁾.