• Archives of Pharmacal Research
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• 제24권3호
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• pp.190-193
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• 2001

Various analogues of 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) such as 2- or 6-(1-hydroxyiminoalkyl)-DMNQs were prepared and evaluated for the antitumor action. (1 -Hydroxyiminoalkyl)-DMNQs derivatives expressed greater antitumor action than (1-hydroxyalkyl) - or acyl-DMNQ derivatives. Moreover, 6-(1-hydroxyiminoalkyl)-DMNQ derivatives expressed higher antitumor action than 2-substituted ones, suggestive of a steric effect. Some of 6-(1-propyloxyalkyl)-DMNQ derivatives with an alkyl group of butyl to octyl moiety showed T/C values of >400%

• Radiation Oncology Journal
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• 제22권4호
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• pp.288-297
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• 2004

목적: 종양 내에서 산소공급 부족현상으로 발생하는 저산소증 조직에서 저온온열치료($42^{circ}C$)와 nicotinamide에 의한 perfusion limited 저산소증의 개선 효과를 마우스 종양 모델을 이용하여 종양 내 $[^18F]FMISO$ 섭취변화를 이용하여 증명할 수 있는지 알아보고자 하였다. 대상 및 방법: C3H 마우스에 $[^18F]FMISO$를 정주하고 11개 장기에서 $\%ID/g$을 구하여 biodistribution을 관찰하였다. 또한 같은 마우스에 동종 종양세포인 SCC7을 이식하여 종양모델을 만들고 저온온열치료($42^{circ}C$)와 nico-tinamide를 투여한 마우스와 대조군 마우스에서 $[^18F]FMISO$의 섭취정도 차이를 $\%ID/g$, autoradiography, PET scan을 시행하여 비교하고자 하였다. 결과: 대조군에서 종양의 FMISO의 섭취는 5.1+/-2.28 $\%ID/g$였고, 종양/근육, 종양/혈액의 섭취비는 2.2와 1.8이었다. 실험군에서는 각각 2.4+/-0.64 $\%ID/g$, 1.4와 1.2를 나타내어 대조군보다 유의하게 낮았다(p<0.021). Autoradiography에서 대조군의 종양 내부에 FMISO가 섭취됨을 확인하였고, 저온온열치료와 nico-tinamide를 투여한 실험군에서는 섭취가 감소된 것을 관찰하였다. 결론: C3H 마우스와 동종 종양세포인 SCC-VII을 이용한 종양모델에서 $[^18F]FMISO$가 종양내에 섭취가 되어 자산소증 종양모델로 적절함을 확인하였고, 저온온열치료($42^{circ}C$)와 nicotinamide에 의한 perfusion limited 저산소증 개선효과를 $[^18F]FMISO$의 종양 내 섭취가 감소하는 것을 통하여 확인할 수 있었다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권13호
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• pp.5181-5186
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• 2014

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-${\beta}$(TGF-${\beta}$) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-${\beta}$ produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-${\beta}$ in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-${\beta}$ using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and $CD4^+Foxp3^+$ Treg cells, and consequently enhanced IFN-${\gamma}$ production by CTLs. Knockdown of tumor-derived TGF-${\beta}$ also significantly reduced the conversion of na$\ddot{i}$ve $CD4^+$ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-${\beta}$ suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-${\beta}$ is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-${\beta}$ may serve as a potential therapeutic approach for cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.1241-1245
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• 2015

Background: Thyroid carcinoma is the most common malignancy of the endocrine organs. Although the majority of thyroid cancer patients experience positive outcomes, anaplastic thyroid carcinoma is considered one of the most aggressive malignancies. Current therapeutic regimens do not confer a significant survival benefit, and new therapies are urgently needed. Oncolytic herpes simplex virus (oHSV) may represent a promising therapy for cancer. In the present study, we investigated the therapeutic effects of a third-generation HSV vector, $G47{\Delta}$, on various human thyroid carcinoma cell lines in vitro. Two subcutaneous (s.c.) models of anaplastic thyroid carcinoma were also established to evaluate the in vivo anti-tumor efficacy of $G47{\Delta}$. Materials and Methods: The human thyroid carcinoma cell line ARO, FRO, WRO, and KAT-5, were infected with $G47{\Delta}$ at different multiplicities of infection (MOIs) in vitro. The survival rates of infected cells were calculated each day. Two s.c. tumor models were established using ARO and FRO cells in Balb/c nude mice, which were intratumorally (i.t.) treated with either $G47{\Delta}$ or mock. Tumor volumes and mouse survival times were documented. Results: $G47{\Delta}$ was highly cytotoxic to different types of thyroid carcinomas. For ARO, FRO, and KAT-5, greater than 30% and 80% of cells were killed at MOI=0.01 and MOI=0.1, respectively on day 5. WRO cells displayed modest sensitivity to $G47{\Delta}$, with only 21% and 38% of cells killed. In the s.c. tumor model, both of the anaplastic thyroid carcinoma cell lines (ARO and FRO) were highly sensitive to $G47{\Delta}$; $G47{\Delta}$ significantly inhibited tumor growth and prolonged the survival of mice bearing s.c. ARO and FRO tumors. Conclusions: The oHSV $G47{\Delta}$ can effectively kill different types of human thyroid carcinomas in vitro. $G47{\Delta}$ significantly inhibited growth of anaplastic thyroid carcinoma in vivo and prolonged animal survival. Therefore, $G47{\Delta}$ may hold great promise for thyroid cancer patients.

• Macromolecular Research
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• 제16권1호
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• pp.15-20
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• 2008

The enhanced permeability and retention (EPR) effect is used extensively for the passive targeting of many macromolecular drugs for tumors. Indeed, the EPR concept has been a gold standard in polymeric anticancer drug delivery systems. This study investigated the tumoral distribution of self-assembled nanoparticles based on the EPR effect using fluorescein and radio-labeled nanoparticles. Self-assembled nanoparticles were prepared from amphiphilic chitosan derivatives, and their tissue distribution was examined in tumor-bearing mice. The size of the nanoparticles was controlled to be 330 run, which is a size suited for opening between the defective endothelial cells in tumors. The long-circulating polymer nanoparticles were allowed to gradually accumulate in the tumors for 11 days. The amount of nanoparticles accumulated in the tumors was remarkably augmented from 3.4%ID/g tissue at 1 day to 25.9%ID/g tissue at 11 days after i.v. administration. The self-assembled nanoparticles were sustained at a high level throughout the 14 day experimental period, indicating their long systemic retention in the blood circulation. The ${\gamma}$-images provided clear evidence of selective tumor localization of the $^{131}I$-labeled nanoparticles. Confocal microscopy revealed the fluorescein-labeled nanoparticles to be preferentially localized in the perivascular regions, suggesting their extravasation to the tumors through the hyperpermeable angiogenic tumor vasculature. This highly selective tumoral accumulation of nanoparticles was attributed to the leakiness of the blood vessels in the tumors and their long residence time in the blood circulation.

• Asian Pacific Journal of Cancer Prevention
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• 제15권5호
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• pp.2353-2358
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• 2014

Purpose: We aimed to detect the expression of HIF-1${\alpha}$, VEGF, HPSE-1 and CD31 in SKOV3 xenografts in nude mice treated with different doses of ionizing radiation, trying to explore the possible mechanism of hypoxia and radioresistance. Methods: Nude mice bearing SKOV3 xenografts were randomly divided into 4 groups: Group A (control group, no ionizing radiation), Group B (treated with low dose of ionizing radiation: 50cGy), Group C (treated with high dose of ionizing radiation: 300cGy), Group D ( combined ionizing radiation, treated with ionizing radiation from low dose to high dose : 50cGy first and 300cGy after 6h interval). The mRNA levels of HIF-1 and VEGF in each group were detected by real time polymerase chain reaction, while HPSE-1 expression was measured by ELISA. The microvessel density (MVD) and hypoxic cells were determined through immunohistochemical (IHC) staining of CD31 and HIF-1a. Results: Significant differences of HIF-1${\alpha}$ mRNA level could be found among the 4 groups (F=74.164, P<0.001): Group C>Group A>Group D> Group B. The mRNA level of VEGF in Group C was significantly higher than in the other three groups (t=-5.267, P=0.000), while no significant difference was observed among Group A, B and D (t=1.528, 1.588; P=0.205, 0.222). In addition, the MVD was shown to be the highest in Group C (t=6.253, P=0.000), whereas the HPSE-1 level in Group A was lower than in Group B (t=14.066, P=0.000) and higher than in Group C (t=-21.919, P=0.000), and similar with Group D (t=-2.066, P=0.058). Through IHC staining of HIF-1a, the expression of hypoxic cells in Group A was (++), Group B was (+), Group C was (+++) and Group D was (+). Conclusion: Ionizing radiation with lowerdoses might improve tumor hypoxia through inhibiting the expression of HIF-1 and HPSE-1, whereas higherdoses worsen tumor hypoxic conditions by up-regulating HIF-1${\alpha}$, HPSE-1, VEGF and CD31 levels. A protocol of low-dose ionizing radiation followed by a high-dose irradiation might at least partly improve tumor hypoxia and enhance radiosensitivity.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.265-271
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• 2014

Interleukin-7 (IL-7) is a potent anti-apoptotic cytokine that enhances immune effector cell functions and is essential for lymphocyte survival. While it known to induce differentiation and proliferation in some haematological malignancies, including certain types of leukaemias and lymphomas, little is known about its role in solid tumours, including breast cancer. In the current study, we investigated whether IL-7 could enhance the in vivo antitumor activity of tumor-reactive $CD8^+$ T cells with induction of IFN-${\gamma}$ in a murine breast cancer model. Human IL-7 cDNA was constructed into the eukaryotic expression plasmid pcDNA3.1, and then the recombinational pcDNA3.1-IL-7 was intratumorally injected in the TM40D BALB/C mouse graft model. Serum and intracellular IFN-${\gamma}$ levels were measured by ELISA and flow cytometry, respectively. $CD8^+$ T cell-mediated cytotoxicity was analyzed using the MTT method. Our results showed that IL-7 administration significantly inhibited tumor growth from day 15 after direct intratumoral injection of pcDNA3.1-IL-7. The anti-tumor effect correlated with a marked increase in the level of IFN-${\gamma}$ and breast cancer cells-specific CTL cytotoxicity. In vitro cytotoxicity assays showed that IL-7-treatment could augment cytolytic activity of $CD8^+$ T cells from tumor bearing mice, while anti-IFN-${\gamma}$ blocked the function of $CD8^+$ T cells, suggesting that IFN-${\gamma}$ mediated the cytolytic activity of $CD8^+$ T cells. Furthermore, in vivo neutralization of $CD8^+$ T lymphocytes by CD8 antibodies reversed the antitumor benefit of IL-7. Thus, we demonstrated that IL-7 exerts anti-tumor activity mainly through activating $CD8^+$ T cells and stimulating them to secrete IFN-${\gamma}$ in a murine breast tumor model. Based on these results, our study points to a potential novel way to treat breast cancer and may have important implications for clinical immunotherapy.

• 대한한의학회지
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• 제30권4호
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• pp.129-141
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• 2009

Objective: This study was to investigate the anti-tumor effect, safety, safety, mechanism and metabolizing enzyme of Agrimonia pilosa LEDEB (APL) in female C57B/L mouse tumor (in vivo). Method: First, to evaluate the antitumor activity of APL, we divided the mice into four groups: normal, control, APL50 (50mg/kg), and APL100 (100mg/kg). LLC-obtained American Type Culture Collection was used. LLC had been inoculated to induce tumors. To measure the anti-tumor effect of APL, we calibrated tumor size and weight. To analyze the mechanism of anti-tumor in APL, we used western blotting and to observe metabolizing enzyme in APL we used to real-time PCR. Result: APL50 and APL100 significantly inhibited tumor growth from 12 days after medicine injected. APL did not induce caspase-dependent apoptosis in LLC-bearing mouse tumor. In APL100, it decreased 41% and 71% in CYP2D22 and CYP3A11, respectively. Conclusion: These results suggest that APL has some anti-tumor effects in female C57B/L mouse tumor. APL should be used carefully with other drugs related with CYP2D22 and CYP3A11.

• 대한핵의학회지
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• 제29권3호
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• pp.332-342
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• 1995

This study was designed to evaluate the effects of various factors on the therapeutic effect of the I-131 labeled anti-carcinoembryonic antigen monoclonal antibody(anti-CEA antibody). Tetrazolium-based colorimetric assay (MTT) was used to compare in vitro cytotoxicity of 3 Korean colon cancer cell lines (SNU-C2A, SNU-C4, SNU-C5) for selection of proper 2 cell lines in this study. The changes of the size of tumor which was xenografted to nude mice (balb/c nu/nu) were compared in 4 groups (group treated I-131 labeled anti-CEA antibody, group treated with non-radiolabeled anti-CEA antibody, group treated with I-131 labeled anti-human chorionic gonadotropin monoclonal antibody (anti-hCG antibody) as nonspecific antibody, and group injected with normal saline as a control). Immunohistochemical staining and in vivo autoradiography were performed after excision of the xenografted tumor. The results were as below mentioned. The in vitro cytotoxic effect of I-131 labeled anti-CEA antibody is most prominent in SNU-C5 cell line between 3 cancer cell lines. The changes of xenografted tumor size in both SNU-C4 and SNU-5S cell tumors at the thirteenth day after injection of the antibodies were smallest in the group treated with I-131 labeled anti-CEA antibody (SNU-C4/SNU-C5; 324/342%) comparing with other groups, group treated with anti-CEA antibody (622/660%), group treated with I-131 anti-hCG antibody (538/546%), and control group(1030/724%)(P<0.02 in SNU-C4 and P<0.1 in SNU-C5 at the 13th day after injection of antibodies). On the thirteenth day after injection of the antibodies nude mice were sacreficed to count the radiouptake of tumor and to check the changes of tumor size. Correlations between radiouptake and change of tumor size were calculated in each groups and significant negative correlation was only obtained in the group treated with I-131 anti-CEA antibody (p<0.05). There were no correlations between antigenic expression of carcinoembryonic antigen and distribution of anti-CEA antibody in both SNU-C4 and SNU-C5 cell tumors on immunoperoxidase staining. On in vivo autoradiography the distributions of anti-CEA antibody were heterogeneous and the intensities of binding were various in SNU-C4 and SNU-C5 cell tumors. It is concluded that I-131 labeled tumor-specific monoclonal antibody, anti-CEA antibody is effective in suppressing the xenografted tumor growth and the effect is influenced by sensitivity of tumor cell itself to the radiolabeled antibody and other local factors instead of specificity of antibody.

• Radiation Oncology Journal
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• 제29권2호
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• pp.83-90
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• 2011

목 적: 이전의 암세포주를 이용한 실험실내 연구에서 플라보피리돌은 암세포의 방사선에 의한 아포토시스를 증가시키는 것을 알 수 있었다. 이번 연구에서는 마우스를 이용한 생체내 실험에서 플라보피리돌의 방사선민감화 효과를 알아보고자 하였다. 대상 및 방법: 마우스 유방암 세포주인 EMT-6를 Balb/c 마우스에 피하주사하여 종양을 만든 후 플라보피리돌 단독 치료군, 방사선 단독 치료군, 방사선과 플라보피리돌 병합 치료군 및 대조군으로 나누어 종양의 성장 속도를 비교 하였다. 플라보피리톨은 2.5 mg/kg을 하루 2회 복강내에 주사하였고, 방사선은 1일 1회, 회당 4 Gy를 조사하여 총 28 Gy를 조사하였다. 각 치료군에서의 종양 성장 곡선을 구하여 비교하였다. 마우스로부터 채취한 종양으로 파라핀 절편을 만틀어 TUNEL 및 면역조직화학염색을 시행하였다. 결 과: 종양 성장을 비교하였을 때 대조군보다 방사선 단독 치료군과 방사선과 플라보피리돌 병합 치료군에서 종양 성장이 지연되는 것을 볼 수 있었다. 그러나 대조군과 플라보피리돌 단독 치료군 사이에서는 종양 성장에 차이가 없었고, 방사선 단독 치료군과 방사선과 플라보피리돌 병합 치료군 사이에서도 차이가 없었다. TUNEL 염색으로 아포토시스율을 비교했을 때 각 치료군 사이에 차이가 없었으며, 면역조직화학염색으로 Ku70 발현을 비교했을 때에도 각 치료군 사이에 차이가 없었다. 결 론: 플라보피리돌은 마우스 유방암 모델에서 방사선민감화 효과를 나타내지 않았다.