Publications (11)37.45 Total impact
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Article: Outcomes of third-line docetaxel-based chemotherapy in advanced gastric cancer who failed previous oxaliplatin-based and irinotecan-based chemotherapies.
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ABSTRACT: Little is known about outcomes in the use of third-line chemotherapy in cases of advanced gastric cancer (AGC). The primary aim of this retrospective study was to evaluate outcomes of docetaxel-based chemotherapy in patients with AGC that progressed after both oxaliplatin-based and irinotecan-based regimens. Eligible patients were those with AGC who had previous chemotherapy including fluoropyrimidine and oxaliplatin as well as fluoropyrimidine and irinotecan and who received subsequent docetaxel-based chemotherapy. Thirty-five patients were retrospectively recruited from 5 medical centers in Korea. Patients received either weekly or 3 weekly with docetaxel +/- cisplatin. Thirty-one out of 35 patients were evaluated for treatment response. A total of 94 cycles of chemotherapy (median, 2; range, 1 to 7) were administered. The overall response rate was 14.3%, and the disease control rate was 45.7%. The median progression-free survival (PFS) was 1.9 months (95% confidence interval [CI], 1.1 to 2.7 months). The median overall survival (OS) was 3.6 months (95% CI, 2.8 to 4.4 months). PFS and OS were significantly prolonged in patients of the Eastern Cooperative Oncology Group, with performance status of 0 or 1 in multivariate analysis (PFS: hazard ratio[HR], 0.411; 95% CI, 0.195 to 0.868; p=0.020 and OS: HR, 0.390; 95% CI, 0.184 to 0.826; p=0.014, respectively). Four of the 35 patients enrolled in the study died due to infection associated with neutropenia. Our findings suggest that salvage docetaxel-based chemotherapy is a feasible treatment option for AGC patients with good performance status (PS), whereas chemotherapy for patients with poor PS (PS≤2) should be undertaken with caution for those who previously failed oxaliplatin- and irinotecan-based regimens.Cancer Research and Treatment 12/2012; 44(4):235-41. -
Article: A phase II trial of Erlotinib in combination with gemcitabine and cisplatin in advanced pancreatic cancer.
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ABSTRACT: Background Gemcitabine has been recognized as a standard chemotherapy in advanced pancreas cancer (APC). We conducted a phase II study of a triple combination regimen (GPT) consisting of gemcitabine (G), cisplatin (P) and erlotinib (T) in patients with APC. Patients and methods Chemotherapy-naïve patients with locally advanced or metastatic, histologically confirmed adenocarcinoma of the pancreas were treated with erlotinib 100 mg daily, 1,000 mg/m(2) of gemcitabine and 25 mg/m(2) of cisplatin administered on days 1 and 8, respectively, every 3 weeks. The primary end point was objective response. Secondary end points included progression-free survival, overall survival and toxicity. The study was designed according to the optimal two-stage design. Results Twenty-two patients were enrolled between June 2009 and August 2010. No complete response was achieved and partial response was observed in 5 patients (26%), Stable disease in 7 (37%), and progressive disease in 7 (37%). The median time to progression was 4.0 months (95% CI: 2.9-5.1 months), and the median overall survival 6.8 months (95% CI: 3.7-9.9 months). The response rate in stage I reached the target (≥3/22, p0 = 10%) established for movement to stage II but this study was determined to close earlier than planned because of unexpected treatment-related deaths (3 patients). Conclusion The triple regimen of GPT is effective for APC. Treatment-related mortalities factored early closure of this GPT protocol. Considering effect and toxicity, this triple regimen seems to offer few benefits to the patients compared with gemcitabine-based doublets. (ClinicalTrials.gov number, NCT00922896).Investigational New Drugs 02/2012; · 3.36 Impact Factor -
Article: Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer.
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ABSTRACT: Activation of sonic hedgehog (Shh) signaling has been implicated in progression of a variety of tumors. In this study, we elucidated a role for Shh in the invasion of gastric tumors and determined the mechanism by which Shh is regulated. Immunohistochemical analysis of 178 primary human gastric tumor biopsies indicated that Shh expression was positively correlated with lymph node metastasis, high lymphatic vessel density, and poor prognosis. In mouse xenograft models of human gastric cancer, enforced expression of Shh significantly enhanced the incidence of lung metastasis compared with nonexpressing controls. Mechanistic investigations revealed that phosphoinositide 3-kinase (PI3K)/Akt inhibition blocked Shh-induced epithelial-mesenchyme transition, the activity of matrix metalloproteinase 9 (MMP-9), and lymphangiogenesis, reducing tumor invasiveness and metastasis. Taken together, our findings establish that Shh signaling promotes the metastasis of gastric cancer through activation of the PI3K/Akt pathway, which leads to mesenchymal transition and MMP-9 activation. These findings offer preclinical validation of Shh as a candidate therapeutic target for treatment of metastatic gastric cancers.Cancer Research 11/2011; 71(22):7061-70. · 7.86 Impact Factor -
Article: The oral iron chelator deferasirox induces apoptosis in myeloid leukemia cells by targeting caspase.
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ABSTRACT: No abstract available.Acta Haematologica 09/2011; 126(4):241-5. · 1.35 Impact Factor -
Article: Metastatic function of BMP-2 in gastric cancer cells: the role of PI3K/AKT, MAPK, the NF-κB pathway, and MMP-9 expression.
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ABSTRACT: Bone morphogenetic proteins (BMPs) have been implicated in tumorigenesis and metastatic progression in various types of cancer cells, but the role and cellular mechanism in the invasive phenotype of gastric cancer cells is not known. Herein, we determined the roles of phosphoinositide 3-kinase (PI3K)/AKT, extracellular signal-regulated protein kinase (ERK), nuclear factor (NF)-κB, and matrix metalloproteinase (MMP) expression in BMP-2-mediated metastatic function in gastric cancer. We found that stimulation of BMP-2 in gastric cancer cells enhanced the phosphorylation of AKT and ERK. Accompanying activation of AKT and ERK kinase, BMP-2 also enhanced phosphorylation/degradation of IκBα and the nuclear translocation/activation of NF-κB. Interestingly, blockade of PI3K/AKT and ERK signaling using LY294002 and PD98059, respectively, significantly inhibited BMP-2-induced motility and invasiveness in association with the activation of NF-κB. Furthermore, BMP-2-induced MMP-9 expression and enzymatic activity was also significantly blocked by treatment with PI3K/AKT, ERK, or NF-κB inhibitors. Immunohistochemistry staining of 178 gastric tumor biopsies indicated that expression of BMP-2 and MMP-9 had a significant positive correlation with lymph node metastasis and a poor prognosis. These results indicate that the BMP-2 signaling pathway enhances tumor metastasis in gastric cancer by sequential activation of the PI3K/AKT or MAPK pathway followed by the induction of NF-κB and MMP-9 activity, indicating that BMP-2 has the potential to be a therapeutic molecular target to decrease metastasis.Experimental Cell Research 07/2011; 317(12):1746-62. · 3.58 Impact Factor -
Article: Characteristics and prognosis of patients with colorectal cancer-associated brain metastases in the era of modern systemic chemotherapy.
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ABSTRACT: Brain metastases (BM) occur in approximately 20-40% of cancer patients. The present study investigated the clinical outcomes of patients with BM from colorectal cancer (CRC) to assess the benefit of systemic chemotherapy (CT) administered after surgical or radiotherapeutic control of BM and to identify independent prognostic factors associated with survival after BM. Between August 2001 and July 2009, 118 patients with symptomatic BM from CRC received either cranial irradiation or craniotomy at two large cancer centers in South Korea. Retrospective review and statistical analysis of clinical characteristics and outcomes were performed for all patients. Median time from diagnosis of metastatic CRC to detection of BM was 12.2 months (range 0-76.2 months). Thirteen patients (11%) exhibited brain involvement at initial presentation. Median survival after BM development was 4.1 months [95% confidence interval (CI) 3.3-4.9 months]. Forty-six patients (40%) had been treated previously with the chemotherapeutic agents fluoropyrimidine, oxaliplatin, and irinotecan. Patients who received CT after BM exhibited significantly improved survival compared with those who did not (12.4 versus 3.1 months, respectively; P < 0.001). Multivariate analysis revealed that CT intervention after presentation with BM was significantly associated with survival after BM, and the adjusted hazard ratio was 0.30 (95% CI 0.17-0.51, P < 0.001). Although BM is a late-stage phenomenon in CRC, approximately two-thirds of patients were still unexposed to irinotecan or oxaliplatin at the development of BM in our study. Thus, additional chemotherapeutic intervention after BM associated with CRC may be beneficial for selected patients.Journal of Neuro-Oncology 02/2011; 104(3):745-53. · 3.21 Impact Factor -
Article: Clinical outcomes and prognostic factors of metastatic gastric carcinoma patients who experience gastrointestinal perforation during palliative chemotherapy.
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ABSTRACT: We conducted the current study to investigate the clinical outcomes of metastatic gastric carcinoma (MGC) patients who experienced gastrointestinal (GI) perforation during palliative chemotherapy and to examine the prognostic factors associated with survival after perforation. We reviewed the medical records of patients at the Center for Gastric Cancer of the National Cancer Center, Korea who developed GI perforation during palliative chemotherapy between January 2001 and December 2008. Of the 1,856 patients who received palliative chemotherapy for MGC, 32 patients (1.7%) developed GI perforation during chemotherapy. Patients with perforation at the primary gastric site were more likely to have ulcerative gastric cancer lesion (90.5 vs. 40.0%, P = 0.034) or gastric tumor bleeding (28.6 vs. 0%, P = 0.298), and less likely to have Bormann type IV (14.3 vs. 60.0%, P = 0.062), than patients with perforation at nongastric sites. In 14 patients (43.8%) who resumed chemotherapy after perforation, the disease control rate was 57.1%, and median overall survival (OS) after perforation was 7.5 months [95% confidence interval (CI), 6.0-9.0 months]. In all patients, median OS following perforation was 4.0 months (95% CI, 1.5-6.6 months), and multivariate analysis revealed that differentiated tumor histology, response to chemotherapy before perforation, and absence of septic shock at time of perforation were significantly associated with favorable OS after perforation. As patients experiencing GI perforation during palliative chemotherapy have heterogeneous clinical presentation, we need to adopt different approaches in the management of the patients that are compatible with the favorable prognostic factors.Annals of Surgical Oncology 12/2010; 17(12):3163-72. · 4.17 Impact Factor -
Article: Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion.
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ABSTRACT: Although dysregulation of bone morphogenetic protein (BMP) signaling has been linked to various types of cancers, the relationship between abnormal activation of these signaling pathways and tumorigenesis is not clear. The purpose of the current study was to clarify how BMP2 is involved in colon cancer aggressiveness. The data showed that SW480 and DLD-1 cells displayed different responses to short- and long-term exposure to BMP2. During the first 24 h of exposure to BMP2, these cells were growth-inhibited, whereas surviving cells became resistant to growth inhibition, showing epithelial-to-mesenchymal transformation (EMT) and enhanced motility and invasiveness. Interestingly, in highly metastatic mesenchymal colon carcinoma cells (CT26), blockade of BMP2 signaling by BMP2 siRNA prevented EMT, motility and invasiveness; rather, blockade of BMP2 signaling caused a mesenchymal-to-epithelial transition (MET). The levels of phosphorylated Akt were very different between the two cell types; the BMP2-sensitive SW480 and DLD-1 cells had much higher levels of expression than the BMP2-resistant SW480 and DLD-1 and CT26 cells. CT26 cells, following exposure to BMP2 and activation of Akt, escaped the EMT-induced cellular motility and invasiveness. Moreover, LY294002 treatment of BMP2-sensitive SW480 cells blocked cell growth and enhanced motility and invasiveness. Together, these results suggest that suppression of the PI3 kinase/Akt pathway is correlated with the development of BMP2 resistance and invasion in BMP2-induced EMT in colon cancer.Oncology Reports 10/2009; 22(3):525-34. · 1.84 Impact Factor -
Article: BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.
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ABSTRACT: Up-regulation of bone morphogenetic proteins (BMPs) and their receptors by tumor is an important hallmark in cancer progression, as it contributes through autocrine and paracrine mechanisms to tumor development, invasion, and metastasis. Generally, increased motility and invasion are positively correlated with the epithelial-mesenchymal transition (EMT). The purpose of the present study was to determine whether BMP-2 signaling to induce gastric cancer cells to undergo EMT-mediated invasion might pass through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Herein we showed that gastric cancer cell lines express all the components of BMP-2 signaling, albeit to different extents. Moreover, an increased concentration of BMP-2 strongly enhanced motility and invasiveness in gastric cancer cells, whereas no increase was observed in cells treated with either Noggin (a BMP-2 inhibitor) or BMP-2 blocking antibodies. The stimulation of BMP-2 in gastric cancer cells induces a full EMT characterized by Snail induction, E-cadherin delocalization and down-regulation, and up-regulation of mesenchymal and invasiveness markers. Furthermore, blockade of BMP-2 signaling by Noggin or BMP-2 blocking antibodies also restored these changes in EMT markers. In addition, phosphorylation of Akt was also enhanced by treatment with BMP-2, but not Noggin or BMP-2 blocking antibodies. Pretreatment of gastric cancer cells with PI-3 kinase/Akt kinase inhibitor (kinase-dead Akt [DN-Akt], Akt siRNA, or LY294002) significantly inhibited BMP-2-induced EMT and invasiveness. Overall, our studies suggest that BMP-2 promotes motility and invasion of gastric cancer cells by activating PI-3 kinase/Akt and that targeting of this signaling pathway may provide therapeutic opportunities in preventing metastasis mediated by BMP-2.Experimental Cell Research 10/2009; 316(1):24-37. · 3.58 Impact Factor -
Article: Sustained co-cultivation with human placenta-derived MSCs enhances ALK5/Smad3 signaling in human breast epithelial cells, leading to EMT and differentiation.
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ABSTRACT: The interaction between mammary epithelial cells and their surrounding microenvironment are important in the development of the mammary gland. Thus, mesenchymal stem cells (MSCs), which retain pluripotency for various mesenchymal lineages, may provide a permissive environment for the morphologic alteration and differentiation of mammary epithelial cells. To this end, we investigated whether the interactions between mammary epithelial cells and human placenta-derived MSCs (hPMSC) affect the morphology, proliferation, and differentiation of epithelial cells in a co-culture system. We show that after co-culture with hPMSCs, human mammary epithelial cell lines (MCF-10F and HEMC) underwent significant morphologic alterations and a dramatic increase in ductal-alveolar branching, which was accompanied by a decrease or loss of the epithelial marker E-cadherin and a gain of the mesenchymal markers, alpha-SMA and vimentin. MCF-10F and HEMC proliferation was also inhibited in the presence of hPMSCs, and this retardation in growth was due to cell cycle arrest. Furthermore, in MCF-10F and HMEC cells, hPMSCs induced the production of lipid droplets, milk fat globule protein, and milk protein lactoferrin, which are markers of functional mammary differentiation. We also noticed an elevation in ALK5 and phosphorylated Smad3 protein levels upon hPMSC co-culture. Strikingly, the changes in morphology, proliferation, and differentiation were reversed by treatment with ALK5 or Smad3 knockdown in MCF-10F/hPMSC co-cultures. Collectively, our findings suggest that co-cultivation with hPMSCs leads to epithelial to mesenchymal transition (EMT) and differentiation of human breast epithelial cells through the ALK5/Smad3 signaling pathway.Differentiation 05/2009; 77(5):450-61. · 2.81 Impact Factor -
Article: Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway.
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ABSTRACT: It is known that the activation of hedgehog (Hh) signaling is involved in the progression and invasion of various tumors, including gastric carcinoma. In this study, we investigated the impact of transforming growth factor (TGF)-beta signaling on the sonic hedgehog (Shh)-mediated invasion of gastric cancer cells. We found that higher concentrations of N-Shh enhanced cell motility and invasiveness in gastric cancer cells, whereas no increase was observed in cells that were treated with KAAD-cyclopamine (a Shh signaling inhibitor) or anti-Shh blocking antibodies. In addition, the N-Shh-induced migration and invasiveness of gastric cancer cells were reduced by treatment with anti-TGF-beta blocking antibody or TGF-beta1 small interfering RNA (siRNA) in presence of N-Shh when compared with control groups. Furthermore, TGF-beta1 secretion, TGF-beta-mediated transcriptional response, expression of activin receptor-like kinase (ALK) 5 protein and phosphorylation of Smad 3 were also enhanced by treatment with N-Shh, but not KAAD-cyclopamine, anti-Shh or TGF-beta1 blocking antibodies. Blockade of the ALK5 kinase in the presence of N-Shh significantly inhibited phosphorylation of Smad 3, activity of matrix metalloproteinases and Shh-induced cell motility/invasiveness. Importantly, transient expression of ALK5 siRNA or Smad 3 siRNA reduced the ability of N-Shh to stimulate migration and invasion of those cells compared with the cells treated with non-specific control siRNA. In summary, these results indicate that Shh promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Additionally, our findings are the first to suggest a role and mechanism for Shh signaling as it relates to the metastatic potential of gastric cancer, thereby indicating potential therapeutic molecular targets to decrease metastasis.Carcinogenesis 04/2008; 29(3):480-90. · 5.70 Impact Factor
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- Experimental Cell Research (2)
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Institutions
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2011
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Korea University
- Graduate School of Medicine
Seoul, Seoul, USA
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2010
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National Cancer Center Korea
Goyang, Gyeonggi, South Korea
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