• Molecules and Cells
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• v.45 no.9
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• pp.622-630
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• 2022

Colorectal cancer (CRC) has a high mortality rate among cancers worldwide. To reduce this mortality rate, chemotherapy (5-fluorouracil, oxaliplatin, and irinotecan) or targeted therapy (bevacizumab, cetuximab, and panitumumab) has been used to treat CRC. However, due to various side effects and poor responses to CRC treatment, novel therapeutic targets for drug development are needed. In this study, we identified the overexpression of EHMT1 in CRC using RNA sequencing (RNA-seq) data derived from TCGA, and we observed that knocking down EHMT1 expression suppressed cell growth by inducing cell apoptosis in CRC cell lines. In Gene Ontology (GO) term analysis using RNA-seq data, apoptosis-related terms were enriched after EHMT1 knockdown. Moreover, we identified the CHOP gene as a direct target of EHMT1 using a ChIP (chromatin immunoprecipitation) assay with an anti-histone 3 lysine 9 dimethylation (H3K9me2) antibody. Finally, after cotransfection with siEHMT1 and siCHOP, we again confirmed that CHOP-mediated cell apoptosis was induced by EHMT1 knockdown. Our findings reveal that EHMT1 plays a key role in regulating CRC cell apoptosis, suggesting that EHMT1 may be a therapeutic target for the development of cancer inhibitors.

• Journal of Digestive Cancer Reports
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• v.7 no.2
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• pp.61-64
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• 2019

We report two cases of patients with unresectable pancreatic cancer treated with neoadjuvant chemotherapy and surgical resection. In the first case, main mass was located at the neck of the pancreas, encasing superior mesenteric artery and peritoneal seeding was suspected. In the second case, main mass was located at the body of pancreas and superior mesenteric artery was encased. Both patients received FOLFIRINOX chemotherapy regimen, consisting of 5-FU, folinic acid, irinotecan and oxaliplatin. In both cases, tumor size decreased and vascular involvement regressed in response to chemotherapy. After subsequent chemoradiation therapy, both patients underwent surgical resection with negative resection margin. The pathological stages were ypT1cN0 and ypT1aN0, respectively. Both patients received postoperative adjuvant chemotherapy with 6 cycles of 5-FU/folinic acid and remained without evidence of disease for more than 6 months after the surgery.

• Journal of Gastric Cancer
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• v.18 no.3
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• pp.305-312
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• 2018

We report a rare case of long-term survival in a patient who received local therapy and salvage chemotherapy for recurrent metastases, along with a literature review. A 65-year-old male patient underwent subtotal gastrectomy for advanced gastric adenocarcinoma. Six months after gastrectomy, 2 metastatic intra-abdominal lymph node enlargements were detected, which were treated with radiotherapy. At 55 months after gastrectomy, an abdominal wall mass was detected, which was treated by surgical resection. The patient received 5-fluorouracil/leucovorin/irinotecan chemotherapy for 27 months before and after radiotherapy and docetaxel chemotherapy for 6 months after surgical resection of the abdominal wall metastasis. At the last visit, 7.8 years since the initial resection of the primary gastric cancer and 6.2 years since detection of the first metastases, the patient was disease-free and required no further chemotherapy. This case suggests that repeated local therapy offers potential for long-term survival in a carefully selected subset of patients with recurrent metastases.

• Journal of Gastric Cancer
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• v.20 no.1
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• pp.95-105
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• 2020

Purpose: Gastric cancer is a highly metastatic malignant tumor, often characterized by chemoresistance and high mortality. In the present study, we aimed to investigate the role of B-cell lymphoma 3 (Bcl-3) protein on cell migration and chemosensitivity of gastric cancer. Materials and Methods: The gastric cancer cell lines, AGS and NCI-N87, were used for the in vitro studies and the in vivo studies were performed using BALB/c nude mice. Western blotting, wound healing assay, Cell Counting Kit-8 assay, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used to evaluate the role of Bcl-3 in gastric cancer. Results: We found that the protein expression of hypoxia (HYP)-inducible factor-1α and Bcl-3 were markedly upregulated under hypoxic conditions in both AGS and NCI-N87 cells in a time-dependent manner. Interestingly, small interfering RNA-mediated knockdown of Bcl-3 expression affected the migration and chemosensitivity of the gastric cancer cells. AGS and NCI-N87 cells transfected with si-RNA-Bcl-3 (si-Bcl-3) showed significantly reduced migratory ability and increased chemosensitivity to oxaliplatin, 5-fluorouracil, and irinotecan. In addition, si-Bcl-3 restored the autophagy induced by HYP. Further, the protective role of si-Bcl-3 on the gastric cancer cells could be reversed by the autophagy inducer, rapamycin. Importantly, the in vivo xenograft tumor experiments showed similar results. Conclusions: Our present study reveals that Bcl-3 knockdown inhibits cell migration and chemoresistance of gastric cancer cells through restoring HYP-induced autophagy.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.3
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• pp.1059-1063
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• 2012

Objective: Angiogenesis represents a key element in the pathogenesis of malignancy. There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic colorectal cancer treated with vascular endothelial growth factor (VEGF)-targeted therapy. The present study was conducted to establish a prognostic model for patients using an oxaliplatin-based or irinotecan-based chemotherapy plus bevacizumab in metastatic colorectal cancer. Methods: Baseline characteristics and outcomes on 170 patients treated with FOLFIRI or XELOX plus anti-VEGF therapy-naive metastatic colorectal cancer were collected from three Turkey cancer centers. Cox proportional hazards regression was used to identify independent prognostic factors for OS. Results: The median OS for the whole cohort was 19 months (95% CI, 14.3 to 23.6 months). Three of the seven adverse prognostic factors according to the Anatolian Society of Medical Oncology (ASMO) were independent predictors of short survival: serum lactate dehydrogenase (LDH) greater than the upper limit of normal (ULN; p<0.001); neutrophils greater than the ULN (p<0.0014); and progression free survival (PFS) less than 6 months (p =0.001). Conclusion: Serum LDH and neutrophil levels were the main prognostic factors in predicting survival, followed by PFS. This model validates incorporation of components of the ASMO model into patient care and clinical trials that use VEGF-targeting agents.

• Radiation Oncology Journal
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• v.31 no.3
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• pp.147-154
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• 2013

Purpose: To evaluate the role of salvage radiotherapy (RT) for the treatment of regional lymph node recurrence (RLNR) after radical surgery in advanced gastric cancer. Materials and Methods: We retrospectively analyzed medical records of 26 patients who underwent salvage treatment after diagnosis of RLNR between 2006 and 2011. Patients with peritoneal seeding or distant metastasis were excluded. Eighteen patients received RT with or without chemotherapy and the other 8 did chemotherapy only without RT. A three-dimensional conformal RT was performed with median dose of 56 Gy (range, 44 to 60 Gy). Sixteen patients had fluoropyrimidine-based chemotherapy, 5 did taxane-based chemotherapy, and irinotecan was applied in 4. Results: With a median follow-up of 20 months (range, 5 to 57 months), median overall survival (OS) and progression-free survival (PFS) after diagnosis of RLNR were 29 months and 12 months in the entire patients, respectively. Radiotherapy (p = 0.007) and disease-free interval (p = 0.033) were statistically significant factors for OS in multivariate analysis. Median OS was 36 months in patients who received RT and 16 months in those who did not. Furthermore, delivery of RT (p < 0.001), complete remission after salvage treatment (p = 0.040) and performance status (p = 0.023) were associated with a significantly better PFS. Gastrointestinal toxicities from RT were mild in most patients. Conclusion: Salvage RT combined with systemic chemotherapy may be an effective treatment managing RLNR from advanced gastric cancer.

• Journal of Gastric Cancer
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• v.10 no.4
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• pp.155-161
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• 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.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.326-331
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• 2012

We recently reported that Val-SN-38, a novel valine ester prodrug of SN-38, had greatly improved the intracellular accumulation of SN-38 in MCF-7 cell line, probably through enhanced uptake via amino acid transporters. In the present study, the efficacy of Val-SN-38 was further investigated both in vitro and in vivo. It was found that the in vitro cytotoxic effect of Val-SN-38 was similar to that of SN-38. Moreover, Val-SN-38 exhibited an equal potency to that of SN-38 in survival experiments in vivo. Because these results seemed to be contrary to the previous finding, further investigation was performed to find out the underlying cause of the contradiction. As only the lactone form is known to have cytotoxic activity, the proportion of lactone in Val-SN-38 and SN-38 was determined, but no differences were found. However, it turned out that Val-SN-38 had poor stability compared with SN-38, which resulted in a decrease in beneficial efficacy for Val-SN-38. Overall, the present study showed that a valine-added prodrug approach could be advantageous provided that the stability of the compound can be ensured. We believe this is a noteworthy study that unravels the discrepancy between intracellular accumulation and efficacy of valine-added prodrug.

• Journal of Yeungnam Medical Science
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• v.39 no.2
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• pp.124-132
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• 2022

Background: Despite recent advances in first-line chemotherapy for advanced pancreatic cancer, standard treatment after the failure of initial chemotherapy has not been established. Hence, we aimed to retrospectively analyze the clinical characteristics and outcomes of second-line chemotherapy in patients with advanced pancreatic cancer. Methods: We reviewed the clinical data of patients with advanced pancreatic cancer who underwent palliative chemotherapy at Kosin University Gospel Hospital between January 2013 and October 2020. Results: Among 366 patients with advanced pancreatic cancer who had received palliative chemotherapy, 104 (28.4%) underwent at least one cycle of second-line chemotherapy. The median age of the patients at the time of initiating second-line treatment was 62 years (interquartile range, 57-62 years), and 58.7% (61 patients) of them were male. The common second-line chemotherapy regimens were 5-fluorouracil (FU) plus leucovorin, irinotecan, and oxaliplatin (33 patients, 31.7%); gemcitabine/nab-paclitaxel (29, 27.9%), gemcitabine±erlotinib (13, 12.5%); and oxaliplatin and 5-FU/leucovorin (12, 11.5%). The median overall survival (OS) and progression-free survival were 6.4 months (95% confidence interval [CI], 4.5-8.6 months) and 4.5 months (95% CI, 2.7-6.3 months), respectively. In a multivariate analysis, poor performance status (PS) (hazard ratio [HR], 2.247; p=0.021), metastatic disease (HR, 2.745; p=0.011), and elevated carcinoembryonic antigen (CEA) levels (HR, 1.939; p=0.030) at the beginning of second-line chemotherapy were associated with poor OS. Conclusion: The survival outcome of second-line chemotherapy for advanced pancreatic cancer remains poor. However, PS, disease extent (locally advanced or metastatic), and CEA level may help determine patients who could benefit from second-line treatment.

• Journal of Digestive Cancer Research
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• v.4 no.2
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• pp.122-126
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• 2016

Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer. The most common cancers involving the leptomeninges are breast, lung cancer and melanoma. However, gastric adenocarcinoma has been rarely reported with leptomeningeal carcinomatosis. The presenting manifestations are usually headache, visual disturbances and seizures. We report a case of leptomeningeal metastasis that presented as a gastric cancer. A 75-year old man was transferred to our hospital for further evaluation and treatment after being diagnosed with adenocarcinoma through endoscopic biopsy during a regular health examination. An abdominal computed tomography (CT) showed AGC, stage IA (cT1N0M0), while an endoscopic examination showed AGC, Borrmann type 2. The patient is currently under observation after undergoing radical subtotal gastrectomy with gastroduodenostomy and subsequent administration of oral chemotherapeutic agents. As an abdominal CT response assessment performed after surgery revealed new metastasis to the liver, the patient received palliative chemotherapy as recurrence was suspected. After receiving chemotherapy in the order of DP (Cisplatin + Docetaxel), FOLFIRI (5-FU + Leucovorin + Irinotecan), an abdominal CT response assessment showed complete response. Since decreased mentality maintained throughout the follow up period based on outpatient clinic, brain MRI was performed and revealed multiple leptomeningeal metastasis. The Patient died 2 days after the diagnosis.