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Antitumor effects of recombinant human interferon α-2a and hydroxyurea against chronic myelogenous leukemia (만성 골수성 백혈병에 대한 유전자 재조합 인터페론 α-2a와 hydroxyurea의 항암효과)

  • Kim, Chang-hwan;Lee, Beom-jun;Park, Jong-hwan;Park, Jae-hak
    • Korean Journal of Veterinary Research
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    • v.40 no.1
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    • pp.166-172
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    • 2000
  • Prior to a clinical trial, the in vitro and in vivo antitumor effects of a new recombinant human interferon ${\alpha}-2a$ (rHu/IFN ${\alpha}-2a$) with/without hydroxyurea (HU) were investigated using chronic myelogenous leukemia (CML)-derived cell lines (K562 and KU812F) and BALB/c nude. mice transplanted with KU812F cells. The rHu/IFN ${\alpha}-2a$ ($10^4-10^6IU/ml$) strongly inhibited proliferation of both cell lines and the combined treatments with HU ($10{\mu}g/ml$) were more effective. In nude mice transplanted with KU812F cells. rHu/IFN ${\alpha}-2a(1{\times}10^6IU$) inhibited tumor growth by 42-65% at 15-21 days post-transplantation (DPT). The combined treatment of rHu/IFN ${\alpha}-2a (5{\times}10^5IU$) with HU (0.25mg/g b.w.) inhibited the tumor growth by 48-67% at 12-21 DPT. In addition, the treatment of rHu/IFN ${\alpha}-2a$ ($5{\times}10^6IU\;or\;1{\times}10^7IU$) rejected tumor transplantation by 40%. These results suggest that the new rHU/IFN ${\alpha}-2a$ alone or with HU is effective on CML cell lines.

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Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

  • Guo, Yan;Wang, Gan;Gao, Wen-Wei;Cheng, Shi-Wen;Wang, Ren;Ju, Shi-Ming;Cao, He-Li;Tian, Heng-Li
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.6
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    • pp.2837-2840
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    • 2012
  • We investigated whether IFN-${\beta}$ inhibits the growth of human malignant glioma and induces glioma cell apoptosis using the human IFN-${\beta}$ gene transfected into glioma cells. A eukaryonic expression vector ($pSV2IFN{\beta}$) for IFN-${\beta}$ was transfected into the glioma cell line SHG44 using liposome transfection. Stable transfection and IFN-${\beta}$ expression were confirmed using an enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was also assessed by Hoechst staining and electron microscopy. In vivo experiments were used to establish a SHG44 glioma model in nude mice. Liposomes containing the human IFN-${\beta}$ gene were injected into the SHG44 glioma of nude mice to observe glioma growth and calculate tumor size. Fas expression was evaluated using immunohistochemistry. The IFN-${\beta}$ gene was successfully transfected and expressed in the SHG44 glioma cells in vitro. A significant difference in the number of apoptotic cells was observed between transfected and non-transfected cells. Glioma growth in nude mice was inhibited in vivo, with significant induction of apoptosis. Fas expression was also elevated. The IFN-${\beta}$ gene induces apoptosis in glioma cells, possibly through upregulation of Fas. The IFN-${\beta}$ gene modulation in the Fas pathway and apoptosis in glioma cells may be important for the treatment of gliomas.

New Model of In-situ Xenograft Lymphangiogenesis by a Human Colonic Adenocarcinoma Cell Line in Nude Mice

  • Sun, Jian-Jun;Jing, Wei;Ni, Yan-Yan;Yuan, Xiao-Jian;Zhou, Hai-Hua;Fan, Yue-Zu
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.6
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    • pp.2823-2828
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    • 2012
  • Objective: To explore a new model of in-situ xenograft lymphangiogenesis of human colonic adenocarcinomas in nude mice. Method: On the basis of establishing subcutaneous xenograft lymphangiogenesis model of human colonic adenocarcinoms, in-situ xenografts were established through the in situ growth of the HT-29 human colonic adenocarcinoma cell line in nude mice. The numbers of lymphangiogenic microvessels, the expression of lymphatic endothelial cell markers lymphatic vessel endothelial hyaloronic acid receptor-1 (LYVE-1), D2-40 and the lymphatic endothelial growth factors vascular endothelial growth factor-C (VEGF-C), -D (VEGF-D) and receptor-3 (VEGFR-3) were compared by immunohistochemical staining, Western bolt and quantitative RT-PCR in xenograft in-situ models. Results: Some microlymphatics with thin walls, large and irregular or collapsed cavities and increased LMVD, with strong positive of LYVE-1, D2-40 in immunohistochemistry, were observed, identical with the morphological characteristics of lymphatic vessels and capillaries. Expression of LYVE-1 and D2-40 proteins and mRNAs were significantly higher in xenograpfts in-situ than in the negative control group(both P<0.01). Moreover, the expression of VEGF-C, VEGF-D and VEGFR-3 proteins and mRNAs were significantly higher in xenografts in-situ (both P<0.01), in conformity with the signal regulation of the VEGF-C,-D/VEGFR-3 axis of tumor lymphangiogenesis. Conclusions: In-situ xenografts of a human colonic adenocarcinoma cell line demonstrate tumor lymphangiogenesis. This novel in-situ animal model should be useful for further studying mechanisms of lymph node metastasis, drug intervention and anti-metastasis therapy in colorectal cancer.

TARGETING RECEPTOR TYROSINE KINASE ON ENDOTHELIAL CELLS IN AN ORTHOTOPIC TUMOR MODEL OF ORAL SQUAMOUS CELL CARCINORMA (구강 편평상피세포암 동위종양 모델에서 내피세포의 수용체 타이로신 인산화효소에 대한 표적치료)

  • Park, Young-Wook;Kim, So-Hee
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.35 no.2
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    • pp.55-65
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    • 2009
  • Purpose: We determined the therapeutic effects of blockade of epidermal growth factor(EGF) and vascular endothelial growth factor(VEGF) receptor tyrosine kinases on the growth of oral squamous cell carcinoma(OSCC) xenografted in athymic nude mice. Experimental Design: We investigated the in vivo antitumor effects of a tyrosine kinase inhibitor for EGFR and VEGFR-2, AEE788 in a mouth floor(orthotopic) tumor model. Nude mice with orthotopic tumors were randomized to receive AEE788, paclitaxel, a combination of AEE788 and paclitaxel, or control. Antitumor mechanisms of AEE788 were determined by immunohistochemical/immunofluorescent and apoptosis assays. Results: Tumors of mice treated with AEE788 demonstrated down-regulation of phosphorylated EGFR, phosphorylated VEGFR and their downstream mediators(pMAPK and pAkt), decreased proliferative index, decreased microvessel density(MVD). As a result, growth of the primary tumor and nodal metastatic potentials were inhibited by AEE788. Conclusion: These data show that EGFR and VEGFR can be molecular targets for the treatment of OSCC.

Cytotoxic Effect of Iljoong-eum on Human Prostate Cancer Cells (일중음의 인체 전립선암 세포에 대한 성장억제 효과)

  • Son, Gi-Jung;Park, Yang-Chun
    • The Journal of Internal Korean Medicine
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    • v.29 no.1
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    • pp.25-31
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    • 2008
  • Objectives : The study was intended to investigate whether Iljoong-eum (IJE) significantly affects proliferation and growth of prostate cancer cells. Materials and Methods : In vitro, after the treatment of DU-145 and PC-3 cells with IJE, we performed Sulforhodamine B (SRB) method. In vivo, a total of 8 male nude mice subcutaneously transplanted with the PC-3 cell line were divided in 2 groups. An experimental group was given IJE orally at a dose of 4.29ml/kg per day from the 8th to 31st day following tumor injection. All mice were observed for 31 days, and sacrificed by CO2 gas asphyxiation at the end of the experiment. The mean tumor volume and body weight of both groups were compared using Student's t-tests. Results : In vitro, IJE inhibited significantly proliferation and growth of DU-145 cells and PC-3 cells. In vivo, IJE inhibited significantly proliferation and growth of PC-3 cells xenografted into athymic nude mice. Conclusions : Our data has shown that IJE is effective in suppressing the growth rate of prostate cancer cells.

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Insulin Promotes Proliferation and Migration of Breast Cancer Cells through the Extracellular Regulated Kinase Pathway

  • Pan, Feng;Hong, Li-Quan
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.15
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    • pp.6349-6352
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    • 2014
  • The present study was undertaken to determine the roles of insulin in the growth of transplanted breast cancer in nude mice, and the proliferation and migration of MCF-7 human breast cancer cells and assess its influence on downstream signaling pathways. In a xenograft mouse model with injection of MCF-7 human breast cancer cells, tumor size was measured every other day. The insulin level and insulin receptor (IR) were increased in the breast cancer patient tissues. Insulin injected subcutaneously around the tumor site in mice caused increase in the size and weight of tumor masses, and promoted proliferation and migration of MCF-7 cells. The effects of insulin on the increase in the proliferation and migration of MCF-7 human breast cancer cells were abolished by pretreatment with the extracellular regulated kinase (ERK) inhibitor PD98059. Insulin increased the phosphorylation of ERK in the MCF-7 cells. These results indicate that insulin promotes the growth of breast cancer in nude mice, and increases the proliferation and migration of MCF-7 human breast cancer cells via the ERK pathway.

Effect of Immune System on Retrovirus-Mediated Herpes Simplex Virus Thymidine Kinase Gene Therapy (면역체계가 Retroviral Vector로 이입한 Herpes Simplex Virus Thymidine Kinase 유전자치료에 미치는 영향)

  • Park, Jae-Yong;Joo, So-Young;Chang, Hee-Jin;Son, Ji-Woong;Kim, Kwan-Young;Kim, Keong-Seok;Kim, Chang-Ho;Park, Jae-Ho;Lee, Jong-Ki;Jung, Tae-Hoon
    • Tuberculosis and Respiratory Diseases
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    • v.46 no.2
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    • pp.229-240
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    • 1999
  • Background: The impact of the immune response on cancer gene therapy using viral vectors to deliver a "suicide gene" is currently unclear. A vigrous immune response targeted at viral proteins or transgene may enhance the efficacy of tumor destruction and even augment responses to tumor antigens. These responses may involve the release of cytokines and stimulation of tumor specific cytotoxic T-lymphocytes that enhance therapeutic efficacy. On the other hand, a vigorous rapid cellular immune response may destroy cells expressing the therapeutic gene and attenuate the response to therapy. Furthermore, development of neutralizing antibody responses may prevent readministration of virus, a potentially significant limitation. Evaluating the significance of these limitations in animal models and developing solutions are therefore of obvious importance. Methods: After retroviral transduction of mouse mesothelioma cell line(AB12) with Herpes Simplex Virus thymidine kinase (HSVtk) gene in vitro, subcutaneous flank tumors were established. To study the effect of intact immune system on efficacy of tumor erradication, the ability of the HSVtk/ganciclovir system to inhibit tumor growth was compared among normal Balb/c mice, immunodeficient Balb/c-nude and SCID mice, and Balb/c mice immunosuppressed with cyclosporin. Results: Ganciclovir treatment resulted in greater inhibition of tumor growth in Balb/c mice compared with immunodeficient Balb/c-nude mice and SCID mice(in immunodeficient mice, there were no growth inhibition by ganciclovir treatment). Ganciclovir treatment resulted in greater inhibition of tumor growth in noncyclosporin (CSA) treated Balb/c mice compared with CSA treated Balb/c mice. On day 8, mean ganciclovir-treated tumor volume were 65% of control tumor volume in Balb/c mice versus 77% control tumor volume in CSA-treated Balb/c mice. This effect was still evident during therapy (day 11 and 13). On day 13, non-CSA treated tumor volume was 35% of control tumor volume versus 60% of control tumor volume in CSA treated Balb/c mice. Duration of expression of HSVtk was not affected by the immunosuppression with CSA. Conclusion: These results indicate that the immune responses against retrovirally transduced cells enhance the efficacy of the HSVtk/ganciclovir system. These findings have important implications for clinical trials using currently available retrovirus vectors as well as for future vector design.

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HiF-1α siRNA and Cisplatin in Combination SuppressTumor Growth in a Nude Mice Model of Esophageal Squamous Cell Carcinoma

  • Liao, Hong-Ying;Wang, Gui-Ping;Gu, Li-Jia;Huang, Shao-Hong;Chen, Xiu-Ling;Li, Yun;Cai, Song-Wang
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.2
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    • pp.473-477
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    • 2012
  • Introduction: The esophagus squamous cell carcinoma (ESCC) is one of the most deadly malignances, and a current challenge is the development of effective therapeutic agents. Our present work addressed the effect of HIF-$1{\alpha}$ siRNA alone or in combination with cisplatin on the growth of ESCC in nude mice. Materials and Methods: Xenografts were established by inoculating ESCC TE-1 cells in nude mice, and transplanted tumors were treated with HIF-$1{\alpha}$ siRNA, cisplatin alone or together. Growth was assessed by measuring tumor volume. HIF-$1{\alpha}$ mRNA and protein expression were detected using RT-PCR and immunohistochemistry, respectively. Apoptosis of ESCC TE-1 cells was analyzed by flow cytometry. Results: In our nude mice model, HIF-$1{\alpha}$ siRNA effectively inhibited the growth of transplanted ESCC, downregulating HIF-$1{\alpha}$ mRNA and protein expression, and inducing ESCC TE-1 cell apoptosis. Notably when combinated with cisplatin, HIF-$1{\alpha}$ siRNA showed synergistic interaction in suppressing tumor growth. Furthermore, the proportion of apoptotic cells in HIF-$1{\alpha}$ siRNA plus cisplatin group was significantly higher than that in cisplatin or HIF-$1{\alpha}$ siRNA-treated groups (P<0.05). Conclusions: Down-regulated HIF-$1{\alpha}$ expression induced by siRNA could effectively suppress the growth of transplanted ESCC $in$ $vivo$. HIF-$1{\alpha}$ siRNA could enhance the cytotoxicity of cisplatin, which suggests that a combination of these two agents may have potential for therapy of advanced ESCC.

Antitumor Responses of Adoptively-Transferred Tumor-Specific T-Cell Cultures in a Murine Lymphoma Model

  • Kim, Hee-Sue;Lee, Hee-Gu;Lim, Jong-Seok;Lee, Ki-Young;Kim, Jae-Wha;Chung, Kyeong-Soo;Choe, Yong-Kyung;Choe, In-Seong;Chung, Tai-Wha;Kim, Kil-Hyoun
    • BMB Reports
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    • v.28 no.6
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    • pp.556-561
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    • 1995
  • The purpose of this study was to establish an in vitro culture method of tumor-specific T cells, and determine the efficacy of the cultured tumor-specific cytotoxic T-lymphocytes (CTL) as an agent of anti-tumor immunotherapy against a murine lymphoma, TIMI.4. Tumor-specific T-lymphocytes derived from C57BL/6 mice (thy-1.2) immune to TIMI.4 were activated by in vitro stimulation with the irradiated TIMI.4 cells, and expanded by restimulation with TIMI.4 in the presence of the concanavalin A-stimulated rat spleen culture supernatant, and splenic antigen-presenting cells. In vitro restimulation enhanced markedly the proportion of $CD8^+$, a predominant surface marker of CTL and the cytotoxic activity in the cultured immune T cell population. The resulting TIMI.4-specific T cells were adoptively transferred into nude mice. The tumor cells residing in the host after 7 days of adoptive transfer to B6.PL (thy-1.1) mice were quantified by use of an antibody directed to the thy-1.2 allele. The TIMI.4 cells in the recipient nude mice were decreased in a dose-dependent manner. Anti-tumor activity of the TIMI.4-specific T cells was also demonstrated by a survival test, where the tumor-bearing nu/nu mice which received the activated T-cells survived about 30% longer than the control mice which received the tumor cells alone. These suggest that adoptive transfer of TIMI.4-specific T cells could be a candidate for effective therapy of the murine lymphoma.

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Antitumor Effects of Water Extracts of Panax notoginseng on NCI-H460 Tumor Regression Model

  • Park, Seung-Chan;Jeong, Tae-Young;Cho, Chong-Kwan;Lee, Yeon-Weol;Yoo, Hwa-Seung
    • The Journal of Korean Medicine
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    • v.31 no.3
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    • pp.8-16
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    • 2010
  • Objective: This study aimed to investigate the antitumor effects of water extracts of Panax notoginseng (WEPN) in NCI-H460 human lung cancer cell xenografted nude mice. Materials and Methods: We cultured NCI-H460 cell lines and xenografted them to nude mice. The mice were divided into 3 groups; positive control group, NCI-H460+150 mg/kg WEPN-treated group, and NCI-H460+300 mg/kg WEPN-treated group. They had been raised and treated in 28 days. We checked their body weight and tumor weight and volumes twice a week and their absolute organ weight and microhistological observation at the final day. We also calculated their tumor inhibition rate (I.R.), mean survival time and percent increase in life span (% ILS). Results: Body weight of WEPN (300 mg/kg) treated mice tended to slightly greater increase than those of the positive control group, but had no significance. Tumor volume (measurement with a caliper) of WEPN-treated mice tended to be lower than that of the positive control group. Inhibition rate (I.R.) of the WEPN group decreased more than the positive control group, but had no significance. Results of tumor weights and volume (plethysmography) had no significance. Mean survival time and percent increase in life span (% ILS) in the WEPN 300 mg/kg treatment group were higher than those of any other group (p<0.05). In absolute organ weights, the WEPN (150-300 mg/kg) treatment group decreased liver weights (p<0.05). Liver tissue of mice treated with WEPN (300 mg/kg) did not show any specific lesions. Conclusion: We suggest that WEPN may have potential as a growth inhibitor of solid tumors induced by NCI-H460 without any side effects. However, this study has limitations in proving anti-tumor effects of WEPN, so further studies to overcome those limitations will be needed.