• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9511-9515
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• 2014

Cholangiocarcinoma (CCA) is a cancer of the bile duct epithelial cells. The highest incidence rate of CCA with a poor prognosis and poor response to chemotherapy is found in Southeast Asian countries, especially in northeastern Thailand and Lao PDR. Cathepsin B is a lysosomal cysteine protease which is regulated by cysteine proteinase inhibitors such as cystatin C. Elevation of cathepsin B levels in biological fluid has been observed in patients with inflammatory diseases and many cancers. We aimed to investigate the serum cathepsin B and cystatin C levels of CCA patients to evaluate the feasibility of using cathepsin B and cystatin C as markers for the diagnosis of CCA. Fifty-six sera from CCA patients, 17 with benign biliary diseases (BBD) and 13 from controls were collected and the cathepsin B and cystatin C levels were determined. In addition, cathepsin B expression was investigated immunohistochemically for 9 matched-pairs of cancerous and adjacent tissues of CCA patients. Serum cathepsin B, but not cystatin C, was significantly higher in CCA and BBD patient groups compared to that in the control group. Consistently, all cancerous tissues strongly expressed cathepsin B while adjacent tissues were negative in 7 out of 9 cases. In contrast, serum cystatin C levels were comparable between CCA and control groups, although serum cystatin C levels in the BBD group was higher than that in the control or CCA groups. When the serum cathepsin B to cystatin C ratio was calculated, that of the CCA group was significantly higher than that of the control group, and, although statistically not significant, the ratio of CCA group showed a trend to be higher than that of the BBD group. Thus, the cathepsin B to cystatin C ratio might be used as an alternative marker for aiding diagnosis of CCA.

• Journal of Gastric Cancer
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• v.16 no.3
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• pp.182-190
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• 2016

Purpose: This study aimed to establish a large-scale database of patients with gastric cancer to facilitate the development of a nationalcancer management system and a comprehensive cancer control policy. Materials and Methods: An observational prospective cohort study on gastric cancer was initiated in 2010. A total of 14 cancer centers throughout the country and 152 researchers were involved in this study. Patient enrollment began in January 2011, and data regarding clinicopathological characteristics, life style-related factors, quality of life, as well as diet diaries were collected. Results: In total, 4,963 patients were enrolled until December 2014, and approximately 5% of all Korean patients with gastric cancer annually were included. The mean age was $58.2{\pm}11.5$ years, and 68.2% were men. The number of patients in each stage was as follows: 3,394 patients (68.4%) were in stage IA/B; 514 patients (10.4%), in stage IIA/B; 469 patients (9.5%), in stage IIIA/B/C; and 127 patients (2.6%), in stage IV. Surgical treatment was performed in 3,958 patients (79.8%), endoscopic resection was performed in 700 patients (14.1%), and 167 patients (3.4%) received palliative chemotherapy. The response rate for the questionnaire on the quality of life was 95%; however, diet diaries were only collected for 27% of patients. Conclusions: To provide comprehensive information on gastric cancer for patients, physicians, and government officials, a large-scale database of Korean patients with gastric cancer was established. Based on the findings of this cohort study, an effective cancer management system and national cancer control policy could be developed.

• Tuberculosis and Respiratory Diseases
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• v.75 no.1
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• pp.9-17
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• 2013

Background: In cancer cells, autophagy is generally induced as a pro-survival mechanism in response to treatment-associated genotoxic and metabolic stress. Thus, concurrent autophagy inhibition can be expected to have a synergistic effect with chemotherapy on cancer cell death. Monensin, a polyether antibiotic, is known as an autophagy inhibitor, which interferes with the fusion of autophagosome and lysosome. There have been a few reports of its effect in combination with anticancer drugs. We performed this study to investigate whether erlotinib, an epidermal growth factor receptor inhibitor, or rapamycin, an mammalian target of rapamycin (mTOR) inhibitor, is effective in combination therapy with monensin in non-small cell lung cancer cells. Methods: NCI-H1299 cells were treated with rapamycin or erlotinib, with or without monensin pretreatment, and then subjected to growth inhibition assay, apoptosis analysis by flow cytometry, and cell cycle analysis on the basis of the DNA contents histogram. Finally, a Western blot analysis was done to examine the changes of proteins related to apoptosis and cell cycle control. Results: Monensin synergistically increases growth inhibition and apoptosis induced by rapamycin or erlotinib. The number of cells in the sub-$G_1$ phase increases noticeably after the combination treatment. Increase of proapoptotic proteins, including bax, cleaved caspase 3, and cleaved poly(ADP-ribose) polymerase, and decrease of anti-apoptotic proteins, bcl-2 and bcl-xL, are augmented by the combination treatment with monensin. The promoters of cell cycle progression, notch3 and skp2, decrease and p21, a cyclin-dependent kinase inhibitor, accumulates within the cell during this process. Conclusion: Our findings suggest that concurrent autophagy inhibition could have a role in lung cancer treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6463-6468
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• 2015

Background: Chemotherapy is one of the common approaches in treatment of cancers, especially leukemia. However, drug resistance phenomena reduce the likelihood of treatment success. Resveratrol is a herbal compound which through complicated processes makes some selected cells sensitive to treatment and induction of apoptosis. In the present study, the effects of resveratrol on the expression of miR 15a and miR16-1 and apoptosis in the CCRF-CEM cell line were investigated. Materials and Methods: The CCRF-CEM cell line was cultured under standard conditions and changes in miR 15a and miR 16-1 expression were analyzed by real time-PCR technique, with attention to reveratrol dose and time dependence. Also, apoptosis is evaluated by flow cytometry using annexin V and PI. Results: CCRF-CEM cells underwent dose-dependent apoptotic cell death in response to resveratrol. MiR 15a and miR 16-1 expression was up-regulated after 24 and 48 hours resveratrol treatment (p<0.05). Conclusions: The results of our study indicate that resveratrol induces apoptosis in a time and dose-dependent manner in CCRF-CEM cells. Also, increased expression level of miR 16-1 and miR 15a by means of resveratrol in CCRF-CEM cells might have a role in apoptosis induction and predisposition. According to our results resveratrol can be regarded as a dietary supplement to improve efficacy of anti-leukemia therapies.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6191-6196
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• 2012

Aims and Background: Traditional chemotherapy strategies for human leukemia commonly use drugs based on cytotoxicity to eradicate cancer cells. One predicament is that substantial damage to normal tissues is likely to occur in the course of standard treatments. Obviously, it is urgent to explore therapies that can effectively eliminate malignant cells without affecting normal cells. Our previous studies indicated that ginsenoside $Rg_1$ ($Rg_1$), a major active pharmacological ingredient of ginseng, could delay normal hematopoietic stem cell senescence. However, whether $Rg_1$ can induce cancer cell senescence is still unclear. Methods: In the current study, human leukemia K562 cells were subjected to $Rg_1$ exposure. The optimal drug concentration and duration with K562 cells was obtained by MTT colorimetric test. Effects of $Rg_1$ on cell cycle were analyzed using flow cytometry and by SA-${\beta}$-Gal staining. Colony-forming ability was measured by colony-assay. Telomere lengths were assessed by Southern blotting and expression of senescence-associated proteins P21, P16 and RB by Western blotting. Ultrastructural morphology changes were observed by transmission electron microscopy. Results: K562 cells demonstrated a maximum proliferation inhibition rate with an $Rg_1$ concentration of $20{\mu}\;mol{\cdot}L^{-1}$ for 48h, the cells exhibiting dramatic morphological alterations including an enlarged and flat cellular morphology, larger mitochondria and increased number of lysosomes. Senescence associated-${\beta}$-galactosidase (SA-${\beta}$-Gal) activity was increased. K562 cells also had decreased ability for colony formation, and shortened telomere length as well as reduction of proliferating potential and arrestin $G_2$/M phase after $Rg_1$ interaction. The senescence associated proteins P21, P16 and RB were significantly up-regulated. Conclusion: Ginsenoside $Rg_1$ can induce a state of senescence in human leukemia K562 cells, which is associated with p21-Rb and p16-Rb pathways.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.4
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• pp.1603-1609
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• 2014

Background: The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median ranging from 6 months to 11.5 years. TP53 is associated with old age, chemotherapy resistance, and worse OS. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized that both TP53 mutations and SNPs at codon 72 would mimic the literature by occurring in a minority of patients, and conferring a worse OS. Materials and Methods: We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n=10). TP53 PCR sequencing was performed using DNA from bone marrow smears. Analysis was accomplished using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Results: Fewer than half of the patients harbored TP53 mutations (40%). There was no significant difference in OS based on gender, AML history, risk-stratified karyotype, or TP53 mutation. There were possible trends toward improved survival among patients less than 60 (11 vs 4 months, p=0.09), Hispanics (8 vs 1 months, p=0.11), and those not harboring SNP P72R (8 vs 2 months, p=0.10). There was a significant improvement in survival among patients with better performance status (28 vs 4 months, p=0.01) and those who did not have a complex karyotype (8 vs 1 months, p=0.03). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Conclusions: Our study confirms previous reports that poor PS and the presence of a complex karyotype are associated with a decreased OS. In our cohort, TP53 mutations were relatively common, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a possible trend toward worse OS among patients with SNP P72R. Larger studies are needed to validate these findings.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4259-4265
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• 2016

Background: Colorectal malignancies with high microsatellite instability (MSI-H), either hereditary (Lynch syndrome) or sporadic, demonstrate better prognosis and altered response to 5FU chemotherapy. It is now recommended to perform MSI testing for all new cases of colorectal cancer regardless of being categorized as hereditary or sporadic. For MSI detection, immunohistochemistry or PCR-based protocols using a cohort of various sets of STR markers are recommended. Here we aimed to evaluate a simplified protocol using just a single STR marker, MT1XT20 mononucleotide repeat, for detection of MSI in Lynch syndrome patients. A Promega five-marker MSI testing panel and immunohistochemistry (IHC) were used as the gold standard in conjunction with MT1XT20. Materials and Methods: Colorectal patients with a positive history of familial cancers were selected by evaluating medical records. Based on Amsterdam II criteria for Lynch syndrome 20 families were short listed. DNA was extracted from formalin fixed paraffin embedded tumour and adjacent normal tissues resected from the index case in each family. Extracted DNA was subjected to MT1XT20 mononucleotide marker analysis and assessment with a commercially available five marker MSI testing kit (Promega, USA). IHC also was performed on tissue sections and the results were compared with PCR based data. Results: Eight (40%), seven (35%) and five (25%) cases were MSI positive using with the Promega kit, IHC and MT1XT20, respectively. Among the markers included in Promega kit, BAT26 marker showed instability in all 8 samples. NR24 and NR21 markers showed instability in 7 (87.5%), and BAT25 and MONO 27 in 6 (75%) and 5 (62.5%). Conclusions: Although MT1XT20 was earlier reported as a valid standalone marker for MSI testing in CRC patients, we could not verify this in our Iranian patients. Instead BAT26 among the markers included in Promega MSI testing kit showed instability in all 8 MSI-H CRC samples. Therefore, it seems BAT26 could act well as a single marker for MSI testing in Iranian CRC patients.

• Korean Journal of Head & Neck Oncology
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• v.18 no.1
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• pp.30-35
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• 2002

Objective: To determine the effectiveness and toxicity of chemoradiation therapy in nasopharyngeal carcinoma by comparing with radiation therapy alone. Materials and Methods: Between October 1989 and July 2000, One hundred eleven patients with newly diagnosed and histologically proven nasopharyngeal carcinoma treated in Department of Radiation Oncology, Asan Medical Center were retrospectively reviewed. Forty-five patients were treated with radiation therapy alone (Group I) and 66 patients were treated with radiation therapy and concurrent cisplatin (Group II). Cisplatin was administered once a week, on the first day of each successive week of treatment, starting on day 1 of radiation therapy and given as a intravenous bolus at a dose of $20mg/m^2$ of body-surface area. Radiation therapy was given in doses of 1.8Gy, once a day, 5 days per week with 4MV or 6 MV photons. Initial field was received a total of 60Gy and a primary tumor and enlarged lymph nodes were boosted with an high dose intracavitory brachytherapy and 3D conformal therapy. Results: The complete response rate was 86.7% in Group I, and was 90.9% in Group II. The 5 year overall survival rate for Group I was 60% and for Group II was 45% (p=0.2520). The 5 year disease free survival rate was 52% versus 45%, respectively (p=0.7507). The median follow up was 44 months versus 34 months, respectively. Conclusion: Analysis of the III patients showed no significant difference in disease free survival and overall survival in two treatment group. This retrospective analysis did not demonstrate benefit with concurrent chemoradiation using cisplatin at a dose of $20mg/m^2$ of body-surface area in treatment result than radiation alone.

• Tuberculosis and Respiratory Diseases
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• v.56 no.2
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• pp.216-220
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• 2004

Because a cavitary pulmonary metastasis is rare, it may not be readily identified. However, various types of cancers can metastasize to the lung in the form of cavities. We report a case of a multiple cavitary metastases to the lung from a cholangiocarcinoma in a 60-year-old man. He complained of generalized weakness and a poor oral intake for 2 months. The plain chest radiography and the chest computed tomography showed multiple small thick-walled cavities and nodules the both lungs. A bronchoscopic examination revealed a focal irregularly elevated surface of the mucosa at the orifice of the superior segment of the right lower lobe and the biopsy demonstrated an infiltrative metastatic adenocarcinoma. The abdomen-pelvis computed tomography showed an ill-marginated and irregularly low-dense area in the right lobe of the liver and a diffuse dilatation of the peripheral intrahepatic bile ducts. The esophagogastroscopy and colonoscopy showed no abnormal findings. It was concluded that the cholangiocarcinoma of the liver metastasized to the lung in the form of cavities. Thereafter, the patient underwent six cycles of the systemic chemotherapy with gemcitabine and cisplatin, and the follow-up imaging studies showed a partial response.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.13
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• pp.5311-5316
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• 2014

Nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as a transcription factor that controls mechanisms of cellular defense response by regulation of three classes of genes, including endogenous antioxidants, phase II detoxifying enzymes and transporters. Previous studies have revealed roles of Nrf2 in resistance to chemotherapeutic agents and high level expression of Nrf2 has been found in many types of cancer. At physiological concentrations, luteolin as a flavonoid compound can inhibit Nrf2 and sensitize cancer cells to chemotherapeutic agents. We reported luteolin loaded in phytosomes as an advanced nanoparticle carrier sensitized MDA-MB 231 cells to doxorubicin. In this study, we prepared nano phytosomes of luteolin to enhance the bioavailability of luteolin and improve passive targeting in breast cancer cells. Our results showed that cotreatment of cells with nano particles containing luteolin and doxorubicin resulted in the highest percentage cell death in MDA-MB 231cells (p<0.05). Furthermore, luteolin-loaded nanoparticles reduced Nrf2 gene expression at the mRNA level in cells to a greater extent than luteolin alone (p<0.05). Similarly, expression of downstream genes for Nrf2 including Ho1 and MDR1 were reduced significantly (p<0.05). Inhibition of Nrf-2 expression caused a marked increase in cancer cell death (p<0.05). Taken together, these results suggest that phytosome technology can improve the efficacy of chemotherapy by overcoming resistance and enhancing permeability of cancer cells to chemical agents and may thus be considered as a potential delivery system to improve therapeutic protocols for cancer patients.