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PubMed | Ajou University, University of Ulsan, Seoul National University, Yonsei University and 2 more.
Type: Clinical Trial, Phase II | Journal: Journal of Korean medical science | Year: 2015

Gaucher disease is a lysosomal storage disease for which enzyme replacement therapy has proven to be effective. A switch-over clinical trial was performed to evaluate the efficacy and safety of Abcertin (ISU Abxis, Seoul, Korea) in subjects with type 1 Gaucher disease who were previously treated with imiglucerase. Five Korean patients with type 1 Gaucher disease were enrolled. Previous doses of imiglucerase ranged from 30 to 55 U/kg every other week. The same dose of Abcertin was administered to all patients for 24 weeks. Primary efficacy endpoints were changes in hemoglobin levels and platelet counts, and the secondary efficacy endpoints included changes in liver and spleen volumes, serum biomarkers, skeletal status and bone mineral density (BMD). During the study period, no statistically significant changes were observed in all parameters including hemoglobin levels and platelet counts, liver and spleen volumes, skeletal status and BMD. Abcertin administration was continued in three patients for another 24 weeks as an extension of the study. Hemoglobin levels and platelet counts were maintained in all three patients. In conclusion, the efficacy and safety of Abcertin are similar to those of imiglucerase, and Abcertin is an effective therapeutic agent for patients with type 1 Gaucher disease (Clinical Trial Registry No. NCT02053896 at www.clinicaltrials.gov).


Lee Y.J.,Center for Clinical Trial | Shim H.S.,Yonsei University | Kang Y.A.,Yonsei University | Hong S.J.,Yonsei University | And 6 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2010

Purpose: This study aimed to determine the dose effect of smoking on the mutational frequency and spectrum of epidermal growth factor receptor (EGFR) gene in Korean non-small cell lung cancer (NSCLC). Methods: Detailed smoking histories were obtained from 324 consecutively enrolled Korean NSCLC patients. Mutational status of EGFR (exon 18-21) was determined using nested polymerase chain reaction amplification. Results: A total of 108 EGFR mutations (33.3%) were identified in 107 patients. Decreased EGFR mutation rate with increased smoking dose was observed, with 48.0% (82 of 171) in never smokers, 23.1% (15 of 65) in former smokers, and 11.4% (10 of 88) in current smokers. The incidence of EGFR mutation was significantly lower in patients who smoked for more than 25 pack-years (P < 0.0001) or who stopped smoking cigarettes less than 10 years ago (P < 0.0001). Mutations in exon 19 or 21 were associated with fewer total smoke years (5.0 vs. 25.0 years in exon 20, P = 0.024), fewer total pack-years (6.3 vs. 38.9 pack-years in exon 20, P = 0.079), and more smoke-free years (11.1 vs. 3.6 years in exon 20, P = 0.027), compared with those in exon 20. Mutations in exon 19 or 21 were associated with female (P < 0.0001), never smoker (P < 0.0001), and adenocarcinoma (P < 0.0001), whereas those in exon 20 were not. Conclusions: Smoking dosage affects the incidence of EGFR mutations. EGFR mutations in exon 19 or 21 are associated with low exposure to cigarette smoke, whereas EGFR mutation in exon 20 is more common in smokers. © 2010 Springer-Verlag.


Jeong J.-Y.,Dong - A University | Jeong J.-Y.,Korea University | Kim K.-S.,CHA Medical University | Moon J.-S.,CHA Medical University | And 8 more authors.
Apoptosis | Year: 2013

The phosphatidylinositol 3-kinase (PI3K) pathway is one of the critical signaling cascades playing important roles in the chemoresistance of human cancer cells, including ovarian cancer. In this study, we investigated the potential of targeting the PI3K p110β-isoform as a novel approach to overcome the chemoresistance in ovarian cancer. The effects on apoptosis, cell viability, proliferation and migration in chemoresistant ovarian cancer cell were determined following targeted p110β inhibition by small interfering RNA (siRNA). Seven paclitaxel (PTX)-resistant sublines (SKpacs and A2780pac) were produced from SKOV3 and A2780 ovarian cancer cell lines. We, first, evaluated the expression of PI3K p110 isoforms in chemosensitive and chemoresistant ovarian cancer cell lines and patient specimens, and found that p110β-isoform was significantly overexpressed both in a panel of ovarian cancer samples, and in PTX-resistant sublines compared with their parent cell lines. RNA interference-mediated p110β silencing augmented PTX-mediated apoptosis (31.15 ± 13.88 %) and reduced cell viability (67 %) in PTX-resistant cells, whereas targeting p110α did not show a significant change in cell viability and apoptosis. In addition, p110β silencing impaired cell proliferation (60 %) in PTX-resistant SKpac cells. We also found the combined treatment group with p110β siRNA and PTX showed a significant inhibition of tumor growth of SKpac cells compared to the PTX-only treated group in a xenograft nude mouse model. Thus, the siRNA-mediated silencing of PI3K p110β resensitizes PTX-resistant ovarian cancer cells, and may be a useful therapeutic strategy for PTX-resistant ovarian cancers. © 2013 The Author(s).


Cho Y.B.,Sungkyunkwan University | Chung H.J.,Catholic University of Korea | Lee W.Y.,Sungkyunkwan University | Choi S.H.,ISU ABXIS Co. | And 3 more authors.
Anticancer Research | Year: 2011

Aim: The aim of this study was to determine whether the relative mRNA expressions of the thymidylate synthase (TYMS) and the excision repair cross-complementing 1 (ERCC1) genes are associated with in vitro chemosensitivity to 5-fluorouracil (5-FU) and oxaliplatin in colorectal cancer, respectively. Patients and Methods: This study included 67 patients with pathologic TNM stage II, III, and IV. TYMS and ERCC1 mRNA expression was determined using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The chemosensitivity was examined using an ATP-based chemotherapy response assay. A high response was defined as a response producing ≥40% reduction in ATP. Results: The mean level of TYMS mRNA expression in the groups with low and high response to 5-FU was 2.35×10 -3 ± 2.16×10 -3 2 -(ΔCt) and 4.54×10 -3 ± 2.46×10 -3 2 -(ΔCt), respectively. The mean level of ERCC1 mRNA expression in the groups with low and high response to oxaliplatin was 13.92×10 -3 ± 9.90×10 -3 2 -(ΔCt) and 23.59×10 -3 ± 5.88×10 -3 2 -(ΔCt), respectively. Groups with high response to 5-FU and oxaliplatin had significantly higher expression of TYMS and ERCC1 mRNA, respectively (p<0.01 and p=0.01, respectively). Conclusion: High expression of TYMS and ERCC1 mRNA was associated with better in vitro chemosensitivity to 5-FU and oxaliplatin, respectively, in patients with colorectal cancer.


Sohn Y.,Seoul National University | Sohn Y.,ISU ABXIS Co. | Lee J.M.,Korea Research Institute of Bioscience and Biotechnology | Park H.-R.,ISU ABXIS Co. | And 3 more authors.
BMB Reports | Year: 2013

Human α-galactosidase A (GLA) has been used in enzyme replacement therapy for patients with Fabry disease. We expressed recombinant GLA from Chinese hamster ovary cells with very high productivity. When compared to an approved GLA (agalsidase beta), its size and charge were found to be smaller and more neutral. These differences resulted from the lack of terminal sialic acids playing essential roles in the serum half-life and proper tissue targeting. Because a simple sialylation reaction was not enough to increase the sialic acid content, a combined reaction using galactosyltransferase, sialyltransferase, and their sugar substrates at the same time was developed and optimized to reduce the incubation time. The product generated by this reaction had nearly the same size, isoelectric points, and sialic acid content as agalsidase beta. Furthermore, it had better in vivo efficacy to degrade the accumulated globotriaosylceramide in target organs of Fabry mice compared to an unmodified version. © 2013 by the The Korean Society for Biochemistry and Molecular Biology.


PubMed | University of New South Wales and Isu Abxis Co.
Type: | Journal: Mediators of inflammation | Year: 2015

Glucocorticoids are commonly used for treating asthma and its exacerbations but have well-recognised adverse effects and are not always effective. Few alternative treatments exist. Using a murine model of an acute exacerbation of asthma, we assessed the ability of ISU201, a novel protein drug, to suppress the inflammatory response when administered after induction of an exacerbation. Sensitised mice were chronically challenged with a low mass concentration of aerosolised ovalbumin, and then received a single moderate-level challenge to simulate an allergen-induced exacerbation. ISU201 was administered to mice 2 and 8 hours later, while pulmonary inflammation and expression of mRNA for chemokines and proinflammatory cytokines were assessed after 4, 12, and 24 hours. Relative to vehicle-treated controls, ISU201 suppressed accumulation of pulmonary neutrophils and eosinophils, while accelerating the decline in CXCL1, TNF-, and IL-6 in lavage fluid and lung tissue. ISU201 significantly reduced peak expression of mRNA for the chemokines Cxcl9 and Cxcl10, the adhesion molecules Icam1 and Vcam1, and the proinflammatory cytokines Il1b, Il12p40, and Csf1. The ability of ISU201 to promote resolution of inflammation suggests that it may have potential as an alternative to glucocorticoids in the management of asthma, including when administered after the onset of an acute exacerbation.


Hur H.,Yonsei University | Kim N.K.,Yonsei University | Kim H.G.,Yonsei University | Min B.S.,Yonsei University | And 4 more authors.
British Journal of Cancer | Year: 2012

Background: This study aims to evaluate the effectiveness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided neoadjuvant chemotherapy for increasing resectability in patients with unresectable colorectal liver metastasis.Patients and methods:Patients were randomised into two groups: Group A was treated by conventional chemotherapy regimen and Group B was treated by chemotherapy regimen according to the ATP-CRA. Three chemotherapeutic agents (5-fluorouracil, oxaliplatin and irinotecan) were tested by ATP-CRA and more sensitive agents were selected. Either FOLFOX or FOLFIRI was administered. Between Group A and B, treatment response and resectability were compared. Results: Between November 2008 and October 2010, a total 63 patients were randomised to Group A (N=32) or Group B (N=31). FOLFOX was more preferred in Group A than in Group B (26 out of 32 (81.3%) vs 20 out of 31 (64.5%)). Group B showed better treatment response than Group A (48.4% vs 21.9%, P=0.027). The resectability of hepatic lesion was higher in Group B (35.5% vs 12.5%, P=0.032). Mean duration from chemotherapy onset to the time of liver resection was 11 cycles (range 4-12) in Group A and 8 cycles (range 8-16) in Group B. Conclusion: This study showed that tailored-chemotherapy based on ATP-CRA could improve the treatment response and resectability in initially unresectable colorectal liver metastasis. © 2012 Cancer Research UK All rights reserved.


Park S.,Yonsei University | Woo Y.,Yonsei University | Kim H.,Yonsei University | Lee Y.C.,Yonsei University | And 3 more authors.
Journal of Gastric Cancer | Year: 2010

Purpose: The purpose of this study was to investigate the reliability and the clinical applicability of the adenosine-triphosphate-based chemotherapy response assay (ATP-CRA) as a method of determining in vitro chemosensitivity in patients with gastric cancer. Materials and Methods: A total of 243 gastric cancer tissue samples were obtained from gastrectomies performed between February 2007 and January 2010. We evaluated the effectiveness of the ATP-CRA assay in determining the chemosensitivity of gastric cancer specimens using eleven chemotherapeutic agents - etoposide, doxorubicin, epirubicin, mytomicin, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel, paclitaxel, methotraxate, and cisplatin - for chemosensitivity studies using ATP-CRA. We assessed the failure rate, the cell death rate, and the chemosensitivity index. Results: The failure rate of ATP-CRA was 1.6% (4/243). The mean coefficient of variation for triplicate ATP measurements was 6.5%. Etoposide showed the highest cell death rate (35.9%) while methotrexate showed the lowest (16.6%). The most active chemotherapeutic agent was etoposide, which most frequently ranked highest in the chemosensitivity test: 31.9% (51/160). Oxaliplatin was more active against early gastric cancers than advanced gastric cancers, whereas docetaxel was more active against advanced cancers. The lymph node negative group showed a significantly higher cell death rate than the lymph node positive group when treated with doxorubicin, epirubicin, and mitomycin. Conclusions: ATP-CRA is a stable and clinically applicable in vitro chemosensitivity test with a low failure rate. The clinical usefulness of ATP-CRA should be evaluated by prospective studies comparing the regimen guided by ATP-CRA with an empirical regimen. © 2010 by The Korean Gastric Cancer Association.


Hur H.,Yonsei University | Kang J.,Yonsei University | Kim N.K.,Yonsei University | Min B.S.,Yonsei University | And 7 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: This study aims to correlate thymidylate synthase (TS) gene polymorphisms with the tumor response to preoperative 5-fluorouracil (5-FU)-based chemoradiation therapy (CRT) in patients with rectal cancer. Methods and Materials: Forty-four patients with rectal cancer treated with 5-FU-based preoperative CRT were prospectively enrolled in this study. Thymidylate synthase expression and TS gene polymorphisms were evaluated in tumor obtained before preoperative CRT and were correlated with the pathologic response, as assessed by histopathologic staging (pTNM) and tumor regression grade. Results: Patients exhibited 2R/3R and 3R/3R tandem repeat polymorphisms in the TS gene. With regard to TS expression in these genotypes, 2R/3RC and 3RC/3RC were defined as the low-expression group and 2R/3RG, 3RC/3RG, and 3RG/3RG as the high-expression group. There was no significant correlation between TS expression and tumor response. There was no significant difference in the tumor response between patients homozygous for 3R/3R and patients heterozygous for 2R/3R. However, 13 of 14 patients in the low-expression group with a G>C single-nucleotide polymorphism (SNP) (2R/3RC [n = 5] or 3RC/3RC [n = 9]) exhibited a significantly greater tumor downstaging rate, as compared with only 12 of 30 patients in the high-expression group without the SNP (2R/3RG [n = 10], 3RC/3RG [n = 9], or 3RG/3RG [n = 11]) (p = 0.001). The nodal downstaging rate was also significantly greater in this low-expression group, as compared with the high-expression group (12 of 14 vs. 14 of 30, p = 0.014). However, there was no significant difference in the tumor regression grade between these groups. Conclusions: This study suggests that SNPs within the TS enhancer region affect the tumor response to preoperative 5-FU-based CRT in rectal cancer. © 2011 Elsevier Inc.


Kim H.-S.,Kyung Hee University | Joo S.H.,Kyung Hee University | Yang D.M.,Kyung Hee University | Lee S.H.,ISU ABXIS Co | And 2 more authors.
Journal of Gastrointestinal and Liver Diseases | Year: 2011

We report a rare case of pancreatic carcinosarcoma in a 48-year-old man. An abdominal ultrasound scan incidentally detected a large heterogeneous mass in the left upper quadrant. CT and MRI scans indicated a rapidly growing unilocular cystic mass in the pancreatic tail. Grossly, the resected pancreatic mass measured 7×5×5 cm and consisted of a unilocular cystic lesion that had several solid mural nodules. Microscopically, the cystic wall showed two carcinomatous components, mucinous cystadenocarcinoma and anaplastic carcinoma. The solid lesion predominantly consisted of pleomorphic spindle cells arranged in interlacing fascicles which had infiltrated the adjacent pancreatic parenchyma. In some areas of this sarcomatous component, anaplastic carcinoma cells intermingled with or transformed into spindle cells. Immunohistochemically, the carcinomatous components were strongly positive for epithelial markers, and transforming anaplastic carcinoma cells were immunoreactive for both epithelial markers and vimentin; in contrast, the sarcomatous component was strongly positive for only vimentin. Additionally, an identical mutation (G to A transition) at codon 12 of K-ras gene and concordant immunoreactivity for p53 protein were detected in the carcinomatous and sarcomatous components. These findings suggested that the pancreatic carcinosarcoma could be of monoclonal origin, and that the sarcomatous component might have arisen from metaplastic transformation of the carcinomatous component.

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