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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. Source

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). Source

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. Source

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. Source

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. Source

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