• Journal of Radiopharmaceuticals and Molecular Probes
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• v.1 no.2
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• pp.123-129
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• 2015

$^{64}Cu$-labeled diacetyl-bis($N^4$-methylthiosemicarbazone) is a promising agent for internal radiation therapy and imaging of hypoxic tissues. In the study, we confirmed hypoxia regions in VX2 tumor implanted rabbits with injection $^{64}Cu$-ATSM and $^{18}F$-FDG using positron emission tomography (PET)/computed tomography (CT). PET images with $^{18}F$-FDG and $^{64}Cu$-ATSM were obtained for 40 min by dynamic scan and additional delayed PET images of $^{64}Cu$-ATSM the acquired up to 48 hours. Correlation between intratumoral $O_2$ level and $^{64}Cu$-ATSM PET image was analyzed. $^{64}Cu$-ATSM and $^{18}F$-FDG were intravenously co-injected and the tumor was dissected and cut into slices for a dual-tracer autoradiographic analysis. In the PET imaging, $^{64}Cu$-ATSM in VX2 tumors displayed a specific uptake in hypoxic region for48 h. The uptake pattern of $^{64}Cu$-ATSM in VX2 tumor at 24 and 48 h did not match to the $^{18}F$-FDG. Through ROI analysis, in the early phase (dynamic scan), $^{18}F$-FDG has positive correlation with $^{64}Cu$-ATSM but late phase (24 and 48 h) of the $^{64}Cu$-ATSM showed negative correlation with $^{18}F$-FDG. High uptake of $^{64}Cu$-ATSM in hypoxic region was responded with significant decrease of oxygen pressure, which confirmed by $^{64}Cu$-ATSM PET imaging and autoradiographic analysis. In conclusion, $^{64}Cu$-ATSM can utilize for specific targeting of hypoxic region in tumor, and discrimination between necrotic- and viable hypoxic tissue.

• Tuberculosis and Respiratory Diseases
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• v.40 no.5
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• pp.495-500
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• 1993

Background: For the relief of the occlusion of major bronchi, laser therapy, radiation therapy or combined therapy is generally used. But the effect of radiation therapy is very slow and not consistent and laser therapy requires expensive equipments and technical expertise with occasional serious side effects. Direct ethanol injection has been widely used for the control of bleeding in gastrointestinal lesion, esophageal varices or renal cell carcinoma with good results. So we tried direct injection of ethanol into the tumor to relieve the obstruction of major bronchus in 11 patients. Method: All procedures were done under the fiberoptic bronchoscopy with continuous oxygen supplement and aliquoted 0.5-1.0 ml of absolute ethanol directly into the tumor through the endobronchial aspiration needle. The tumor was endoscopically removed with a biopsy forceps immediately after ethanol injection. The whole procedure was repeated 3-4 days interval until the lumen opens. Usually after 2-3 trials of ethanol injection, the lumen opened up. Results: The immediate effect of ethanol injection was whitening of the mucosa and prompt cessation of bleeding. The late effect was necrosis of the tumor. The final results of this procedure were improvement of symptoms and reexpnasion of the lung in all patients. $FEV_{1.0}$ and FVC were improved and $PaO_2$ was increased from $68.1{\pm}9.2$ mmHg to $83.9{\pm}8.1$ mmHg, $SaO_2$: from $94{\pm}8.5%$ to $96.6{\pm}1.1%$, and $AaDO_2$ was reduced from $26.5{\pm}8.5$ mmHg to $10.9{\pm}9.1$ mmHg. Conclusion: Direct ethanol injection into the tumor tissue is a rapid, cheap and relatively safe method of relieving the complete occlusion of major bronchus.

• Korean Journal of Head & Neck Oncology
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• v.25 no.1
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• pp.3-7
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• 2009

Background and Objectives : Panax ginseng C.A. Meyer is a medical plant that has been widely utilized as a tonic and nutritional agent since ancient times in Korea. Ginseng has anti-metastatic property of cancer and immunomodulating activity. The novel acidic polysaccharide compound(MB40) was isolated from the leaves of Panax ginseng C.A. Meyer. To determine immunomodulating activities of MB40, we evaluate anti-cancer and anti-metastatic effects of MB40 in tumor bearing immune competent mice. Material and Methods : C3H mice were divided into three equal groups(Cisplatin treatment group, MB40 treat-ment group, Cisplatin and MB40 treatment group) and were transplanted SCC(Squamous Cell Carcinoma) cells(2${\times}$106) to the lateral side of abdomen. From day 4 after transplantation, MB40 was administrated at dose of 10mg/kg, respectively, every other day by intratumoral injection. Cisplatin was systemically administrated at doses of 1mg/kg, respectively, every week by intraperitoneal injection. Results : 5 days after administration, tumors can be palpated in every mice group. After 13 days of administration, the mice group to which MB40 were administrated exhibited reduction in tumor size respectively, compared to cisplatin group. Overall status of mice such as body weight and activity were superior in MB40 group than cisplatin group. Conclusion : The result of this study indicates MB40 may have significant therapeutic effect and decreases complications induced by systemic chemotheraphy. MB40 may be developed as a novel and potent immunotropics to improve the cell immune system and anti-cancer drug for the treatment of cancer patients in head and neck squamous cell carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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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.

• Radiation Oncology Journal
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• v.34 no.3
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• pp.223-229
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• 2016

Purpose: This study is to investigate the effect of captopril when combined with irradiation. Materials and Methods: 4T1 (mouse mammary carcinoma) cells were injected in the right hind leg of Balb/c mice. Mice were randomized to four groups; control (group 1), captopril-treated (group 2), irradiated (group 3), irradiated and captopril-treated concurrently (group 4). Captopril was administered by intraperitoneal injection (10 mg/kg) daily and irradiation was delivered on the tumor-bearing leg for 15 Gy in 3 fractions. Surface markers of splenic neutrophils (G-MDSCs) and intratumoral neutrophils (tumor-associated neutrophils [TANs]) were assessed using flow cytometry and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 alpha ($HIF-1{\alpha}$) of tumor was evaluated by immunohistochemical (IHC) staining. Results: The mean tumor volumes (${\pm}$standard error) at the 15th day after randomization were $1,382.0({\pm}201.2)mm^3$ (group 1), $559.9({\pm}67.8)mm^3$ (group 3), and $370.5({\pm}48.1)mm^3$ (group 4), respectively. For G-MDSCs, irradiation reversed decreased expression of CD101 from tumor-bearing mice, and additional increase of CD101 expression was induced by captopril administration. Similar tendency was observed in TANs. The expression of tumor-necrosis factor-associated molecules, CD120 and CD137, are increased by irradiation in both G-MDSCs and TANs. Further increment was observed by captopril except CD120 in TANs. For IHC staining, VEGF and $HIF-1{\alpha}$ positivity in tumor cells were decreased when treated with captopril. Conclusion: Captopril is suggested to have additional effect when combined to irradiation in a murine tumor model by modulation of MDSCs and angiogenesis.

• Journal of Nutrition and Health
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• v.36 no.2
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• pp.133-146
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• 2003

This study was performed to investigate the in vitro and in vivo anticancer effects of persimmon leaf extracts on human gastric cancer cells. In vitro anticancer effects of persimmon leaf extracts (water extract at 8$0^{\circ}C$ for 3 hours, water extract at room temperature for 48 hours, 50% ethanol extract at 8$0^{\circ}C$ for 3 hours, 50% ethanol extract at room temperature for 48 hours, 75% ethanol extract at 8$0^{\circ}C$ for 3 hours and 75% ethanol extract at room temperature for 48 hours) on SNU16 (Korean gastric cancer cell) were investigated by MTT assay. Persimmon leaf extracts exhibited strong in vitro anticancer effects. We found that the higher the ethanol content of the solvent, the stronger the in vitro anticancer effects. Extraction yields, contents of flavonoids, vitamin A, vitamin C and vitamin E were measured. We found that the higher the ethanol content of the solvent, the higher the extraction yields and the contents of flavonoids, vitamin A and vitamin E. Among persimmon leaf extracts, 75% ethanol 8$0^{\circ}C$ extract showed the highest extraction yield, the highest contents of flavonoids, vitamin A and vitamin E and exhibitied the strongest in vitro anticancer effect on SNU16. Therefore, 75% ethanol 8$0^{\circ}C$ extract was chosen as the material to investigate in vivo anticancer effects. In vivo anticancer effect of persimmon leaf 75% ethanol 8$0^{\circ}C$ extract was investigated in SNU16 transplanted nude mice. Twenty five female nude mice (BALB/c) were blocked into five groups according to body weight and raised for 4 weeks with diets containing 4% (w/w), 8% (w/w) persimmon leaf 75% ethanol 8$0^{\circ}C$ extract, with IT (intratumoral) injection treatment with 1.65 mg/100 $\mu$1, 3.3 mg/100 $\mu$1 concentration every other day 3 weeks after SNU16 was transplanted. Persimmon 75% ethanol 8$0^{\circ}C$ extract significantly lowered tumor weight and tumor volume in SNU16 transplanted nude mice. Tumor weight and tumor volume in all experimental groups were significantly lower than those in the control group. Helper T cell (CD4) levels of mice injected with 3.3 mg/100 $\mu$1 extract significantly increased. Cytotoxic T cell (CD8) levels in all experimental groups significantly increased and helper/cytotoxic T cell ratios in all experimental groups significantly decreased. Natural killer cell and MHC class II molecule in all experimental groups significantly increased. In conclusion, persimmon leaf 75% ethanol 8$0^{\circ}C$ extract exhibited strong in vitro and in vivo anticancer effects against SNU16 cells and it increased cytotoxic T cell, natural killer cell and MHC classII molecule in experimental groups in SNU16 transplanted nude mice.

• Radiation Oncology Journal
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• v.21 no.3
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• pp.207-215
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• 2003

Purpose: Extracellular signal-regulated kinase (ERK), which is part of the mitogen-activated protin kinase cascade, opposes initiation of the apoptotic cell death which is programmed by diverse cytotoxic stimuli. In this regard, the inhibition of ERK may be useful in improving the therapeutic efficacy of established anticancer agents. Materials and Methods: Murine hepatocarcinoma, HCa-I is known to be highly radioresistant with a TCD50 (radiation dose yield in $50\%$ cure) of more than 80 Gy. Various anticancer drugs have been found to enhance the radioresponse of this particular tumor but none were successful. The objective of this study was to explore whether the selective inhibition of MEK could potentiate the antitumor efficacy of radiation in vivo, particularly in the case on radioresistant tumor. C3H/HeJ mice hearing $7.5\~8\;mm$ HCa-I, were treated with PD98059(intratumoral injection of $0.16\;\mug/50\;\mul$). Results: Downregulation on ERK by PD98059 was most prominent 1h after the treatment. In the tumor growth delay assay, the drug was found to Increase the effect of the tumor radioresponse with an enhancement factor (EF) of 1.6 and 1.87. Combined treatment of 25 Gy radiation with PD98059 significantly increased radiation induced apoptosis. The peak apoptotic index (number on apoptotic nuclei in 1000 nuclei X100) was $1.2\%$ in the case of radiation treatment alone, $0.9\%$ in the case of drug treatment alone and $4.9\%,\;5.3\%$ in the combination treatment group. An analysis of apoptosis regulating molecules with Western blotting showed upregulation of p53, p$p21^{WAF1/CIP1}\;and\;Bcl-X_s$ in the combination treatment group as compared to their levels in either the radiation alone or drug alone treatment groups. The level of other molecules such as $Bcl-X_L4, Bax and Bcl-2 were changed to a lesser extent. Conclusion: The selective inhibition of MEK in combination with radiation therapy may have potential benefit in cancer treatment.

• Korean Journal of Food Science and Technology
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• v.36 no.1
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• pp.141-146
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• 2004

Fungal products indirectly mediate anti-tumor effects in vitro and in vivo. To investigate whether Lentinus edodes might possess direct anti-tumor substance, L. edodes was extracted and tested on human papillomavirus (HPV) 16 oncogenes-associated animal tumor cells (TC-1) and in an animal tumor model. Only water extract displayed direct anti-proliferative effects in TC-1 tumor cells in vitro. This inhibition was dose-dependent, and inhibitory concentration ($IC_{50}$) was $800\;{\mu}g/mL$. Fungal extracts also showed growth inhibition to human cervical cancer cells (CaSki and HeLa) similarly to TC-1 tumor cells. When fungal extracts were added at a high dose (1.5 mg/mL), cell growth was inhibited within 6 hr following extract treatment. Cell growth inhibition was blocked by heat treatment, but not by low pH, which is indicative of heat sensitivity of this anti-proliferative substance. Cell growth suppression was mediated by apoptosis, as determined by Annexin V and propidium iodide staining. When challenged with TC-1 cells, direct intratumoral injection of fungal extracts resulted in some positive effect on tumor growth inhibition, as compared to oral delivery. Results suggest that heat labile substance of L. edodes suppresses growth of HPV oncogenes-associated tumor cells through apoptosis.