Sang-Bae Han

Causal relationship between the loss of RUNX3 expression and gastric cancer.

Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells. Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and a mutation (R122C) occurring within the conserved Runt domain abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.

Stimulation of humoral and cell mediated immunity by polysaccharide from mushroom phellinus linteus

Polysaccharide was purified from mycelial culture of Phellinus linteus (PL) and its effect on immunocompetence of normal splenocytes was observed. Overall in vitro immune function was enhanced by addition of PL into culture of mouse spleen lymphocyte and i.p. injection into mouse, while beta-glucans and other polysaccharides only raised the level of T lymphocyte-mediated immunity. PL stimulated immune functions of T lymphocytes, such as proliferation of T lymphocyte induced by mixed lymphocytes reaction and cytotoxicity of cytotoxic T cells responding to alloantigen. Nonspecific immune functions mediated by natural killer cells and macrophages were increased by treatment of PL in vivo and in vitro. PL also stimulated humoral immune function positively, such as T-dependent and T-independent primary antibody response, and acted as a polyclonal activator on B cell. PL exhibited a wider range of immunostimulation and antitumor activity than other polysaccharides isolated from Basidiomycetes.

The inhibitory effect of polysaccharides isolated from Phellinus linteus on tumor growth and metastasis.

It was previously reported that polysaccharides (PL) isolated from Phellinus linteus strongly stimulated cell-mediated and humoral immunity. This study was undertaken to investigate the immunochemotherapeutic activity of PL against tumor growth and metastasis. PL alone significantly prolonged the survival rate of B16F10-implanted mice, inhibited tumor growth in NCI-H23-implanted nude mice, and reduced the frequency of pulmonary metastasis of B16F10 melanoma. Adriamycin significantly inhibited tumor growth, but only slightly inhibited metastasis. The combination therapy with PL and adriamycin was more effective in inhibiting tumor growth, but not metastasis. PL did not induce direct toxicity in cancer cells, which is characteristic of immunotherapeutics. In conclusion, PL might be of use in immunochemotherapy of cancer because of its effective activities on tumor growth and metastasis through the immunopotentiation of the patients without toxicity.

Characteristic immunostimulation by angelan isolated from Angelica gigas Nakai.

The immunopharmacological characteristics of angelan, a polysaccharide purified from Angelica gigas Nakai, were investigated in relation to the specificity to immune cells. The treatment of angelan increased the expression of IL-2, IL-4, IL-6, and IFN-gamma. The expression of IL-6 and IFN-gamma was rapidly augmented but that of IL-2 responded later. In the case of IL-4, angelan stimulated at early time after exposure but down-regulated thereafter. These results suggested that macrophages and natural killer cells involved in nonspecific immunity were primarily activated and helper T cells were secondarily affected by angelan. Angelan also had lympho-proliferative potential to B cells, specifically. The specificity of angelan was also elucidated in a cell fractionation experiment. The activated B cells by angelan also increased antibody production. The direct activation of B cells, macrophages, and accessory cells and the indirect activation of helper T cells coordinately increased immune functions such as in vitro and in vivo T-dependent immunization and antibody production. The experiment of host resistance to syngeneic tumors also showed that angelan potentiated the immune functions. In conclusion, angelan, a purified polysaccharide from an oriental herbal drug, showed characteristic immunostimulation, which was different from clinically used polysaccharides such as lentinan and PSK.

T-cell specific immunosuppression by prodigiosin isolated from Serratia marcescens

Prodigiosin was isolated from the culture broth of Serratia marcescens B-1231. This compound inhibited the T-cell mediated immune responses such as concanavalin-A induced proliferation, mixed lymphocyte response, local graft vs host reaction and T-dependent antibody response at non-toxic concentrations. However, prodigiosin did not affect B-cell mediated immune functions such as lipopolysaccharide-induced proliferation and-activated polyclonal antibody production at the same concentrations. Prodigiosin did not cause death in vitro to lymphocytes at effective concentrations (< 100 nM) and also did not show toxicity in vivo to lymphoid organs at effective dosages (10 and 30 mg/kg). The pharmacological potencies were comparable to the activities of other T-cell specific immunosuppressants such as cyclosporin A and FK-506. In conclusion, it might be suggested that prodigiosin could be used as an immunosuppressant in clinical and immunological studies.

A novel stereo-selective sulfonylurea, 1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one, has antitumor efficacy in in vitro and in vivo tumor models.

The antitumor activities of novel 1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-ones were studied to determine the potential of these compounds as antitumor candidates. The agents studied were: DW2143 (1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one), a racemic mixture, and DW2282 [(4S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one], an S-isomer. DW2143 and DW2282 suppressed the in vitro growth of tumor cells at lower concentrations than doxorubicin, but tumor specificity was not observed between the compounds. These compounds when administered orally were not active in syngeneic models of murine Colon 26 adenocarcinoma and L1210 leukemia. However, DW2143 suppressed the growth of SW620 (human colon cancer) and NCI-H23 (human lung cancer) cells in nude mice, inhibiting tumor growth by 87 and 67%, respectively. DW2282 was a more potent inhibitor of SW620 tumor cell growth in nude mice and was also lower in toxicity than DW2143. Moreover, DW2282 did not produce a series of toxic symptoms caused by the aniline metabolites of sulfonylureas, including hypoglycemia. These results suggest that DW2282, an S-isomer, could be a novel antitumor candidate with higher specificity and lower toxicity than other orally active sulfonylureas.

Activation of NF-κB/Rel in angelan-stimulated macrophages

In our previous studies we showed that the primary target cell of angelan, a polysaccharide purified from Angelica gigas Nakai, is a macrophage (Han et al., 1998). In the present study we examined the effect of angelan on iNOS, IL-1β, and TNF-α transcription in mouse macrophage line RAW 264.7. We show that angelan produces a marked induction of iNOS, IL-1β, and TNF-α transcription by RAW 264.7 cells. Since these gene transcriptions have been recently shown to be under the control of NF-κB/Rel family of transcription factors, we assessed the effect of angelan on NF-κB/Rel using a electrophoretic mobility shift assay. Treatment of RAW 264.7 cells with angelan produced strong induction of NF-κB/Rel binding. Treatment of RAW 264.7 cells with angelan slightly induced AP-1 binding activity, whereas Oct binding was not affected by angelan. Angelan stimulated macrophages to activate NF-κB/Rel, whereas neither B-cells nor T-cells were affected by the angelan. In conclusion, we demonstrate that the stimulation effect of angelan on macrophage is mediated by specific activation of NF-κB/Rel.

Inhibition of human ovarian tumor growth by cytokine-induced killer cells.

Despite the recent improvement in the treatment of ovarian cancer, this disease is still leading cause of cancer death in women. In this study, the anti-tumor activity of cytokine-induced killer (CIK) cells against human ovarian cancer was evaluatedin vitro andin vivo. Although CD3+CD56+ cells were rare in fresh human peripheral blood mononuclear cells, they could expand more than 1,000-fold on day 14 in the presence of anti-CD3 antibody plus IL-2. At an effector-target cell ratio of 30:1, CIK cells destroyed 45% of SK-OV-3 human ovarian cancer cells, which was determined by the51Cr-release assay. In addition, CIK cells at a dose of 23 million cells per mouse inhibited 73% of SK-OV-3 tumor growth in nude mouse xenograft assay. This study suggests that CIK cells may be used as an adoptive immunotherapy for patients with ovarian cancer.

Cytotoxicity of urushiols isolated from sap of Korean lacquer tree (Rhus vernicifera stokes)

Cytotoxicities of four urushiols, congeners isolated from the sap of Korean lacquer tree (Rhus vernicifera Stokes), to 29 human cancer cell lines originated from 9 organs were evaluated. Their values of 50% growth inhibition were below 4 μg/ml, and showed cell line specific cytotoxicity. The present result is the first report on the cytotoxicity of urushiols suggesting that they would have an anticancer activity to human cancer cells.

Immunomodulating activity of a polysaccharide isolated from mori cortex radicis

The immunomodulating activity of a polysaccharide isolated fromMorus alba (PMA) root bark was examined in murine splenic lymphocytes. PMA enhanced proliferation of splenic lymphocytes in a synergistic manner in the presence of mitogens. However, PMA suppressed primary IgM antibody production, from B cells, which was activated with lipopolysaccharide, a polyclonal activator, or immunized with a T-cell dependent antigen sheep red blood cells. Our observations showed that the immunomodulating activity of PMA increased lymphocyte proliferation and that PMA decreased antibody production from B cells, which was distinct from those of other plant-originated polysaccharides.