Telomeres are nucleoprotein structures that compose the ends of eukaryotic chromosomes and that regulate chromosome integrity and cell proliferative lifespan. Stabilization of telomere length correlates with cell immortalization, and constitutive activation of telomerase is observed in most human cancers, suggesting that telomere maintenance plays an important role in malignant transformation and possibly aging. However, several lines of evidence indicate that alterations in telomere biology both suppress and facilitate malignant transformation. Moreover, recent observations indicate that telomerase expression plays important regulatory functions beyond the maintenance of telomere length in both normal and malignant cells. Understanding these additional functions of telomerase promise to provide further insight into both normal and malignant cell physiology.
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Prognostic Implication of Telomerase Activity in Patients with Brain Tumors Choong Hyun Kim, Jin Hwan Cheong, Koang Hum Bak, Jae Min Kim, Suck Jun Oh Journal of Korean Medical Science.2006; 21(1): 126. CrossRef
PURPOSE The potential therapeutic application of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in the treatment of multiple myeloma (MM), was recently proposed. However, there have been some problems with the use of TRAIL, due to the appearance of TRAIL-resistant cells in MM. The effect of arsenic trioxide (As2O3) on the rate of apoptosis induced by TRAIL was evaluated in MM cells. MATERIALS AND METHODS Using TRAIL-sensitive (RPMI- 8226) and TRAIL-resistant (ARH-77 and IM-9) MM cell lines, the cell viability, induction of apoptosis, and change in the caspases were examined after treatment with TRAIL alone, or in combination with various concentrations of As2O3. RESULTS Incubating the cell lines with As2O3 augmented the TRAIL-induced apoptosis in the MM cell lines, according to the As2O3 concentration. Apoptosis was mediated through caspase activation. When TRAIL was used alone, caspase8 was activated in the RPMI-8226 cell lines, but not in the ARH-77 and IM-9 cell lines. When As2O3 was added to TRAIL, caspase-9 was activated in the ARH-77 and IM-9 cells. CONCLUSION The use of As2O3, in combination with TRAIL, would help enhance the level of TRAIL-induced apoptosis, and overcome the TRAIL-resistance, in MM cells.
PURPOSE Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA onto chromosome ends to compensate for sequence loss during DNA replication. It has been detected in 85~90% of all primary human cancers, implicating that its apparent reactivation in tumors may play a role in the tumorigenic process. The purpose of this study was to evaluate telomerase activity in stomach cancer, and to determine whether methacarn-fixed paraffin-embedded tissues can replace frozen tissue sections for the telomerase (TRAP) assay. MATERIALS AND METHODS: Frozen and corresponding methacarn-fixed paraffin-embedded tissue samples were obtained from 51 patients with gastric adenocarcinoma and analyzed for telomerase activity by using a TRAPeze ELISA kit. RESULTS: Telomerase activity was detected in 37 (73%) frozen samples, and in 13 (25%) methacarn-fixed paraffin blocks. Telomerase activity was well correlated with depth of invasion (p=.037) and tumor differentiation (p=.022). CONCLUSION: These data suggest that reactivated telomerase may play a significant role in the tumorigenesis of gastric cancer and may reflect the malignant potential of the tumor. It is noteworthy that methacarn- fixed tissue cannot as yet substitute for the frozen tissue in the TRAP assay.
Jun Hwa Hwang, Kyu Sik Kim, Yu Il Kim, Eun Joung Kim, Kyung Hwa Park, Gye Jung Cho, Jin Young Ju, Sung Chul Lim, Young Chul Kim, Kyung Ok Park, Jong Tae Park, Sung Ja Ahn
Cancer Res Treat. 2003;35(6):483-488. Published online December 31, 2003
PURPOSE Although 80~90% of patients with lung cancer are smokers, only 11% of smokers develop lung cancer. Genetic susceptibility according to the polymorphism of the epoxide hydrolase (mEPHX) gene and homozygous deletion of GSTM1 (M1 subunit of Glutathione S transferase) was studied in this case control study. MATERIALS AND METHODS: Genomic DNA from 76 subjects with lung cancer (40 squamous cell carcinoma, 13 adenocarcinoma, 10 subtype undetermined non-small cell lung cancer, and 13 small cell lung carcinoma) and 62 age- matched controls were extracted from peripheral white blood cells. PCR and RFLP (restriction fragments length polymorphism) with restriction enzyme (RsaI) and automatic sequencing were used for mEPHX genotyping (T-->C, Tyr113His) in exon 3 and (A-->G, His139Arg) in exon 4. Looking for homozygous deletions of GSTM1, multiplex PCR with primers for the GSTM1 gene and coagulation factor V gene (as positive control) were performed. RESULTS: The age distribution between the cancer and control groups were similar (63.6 7.2 vs. 61.1 7.9 years). The lung cancer group, however, had more smokers (73.3%, 44/60) than the control group (21/54, 38.9%, p<0.001). The rate of homozygous deletion of the GSTM1 gene was significantly higher in the lung cancer group (65.8%, 50/76) than in the control group (46.8%, 29/62, p<0.05), causing the relative risk of GSTM1 deletion for lung cancer as 2.19 (95% CI: 1.10~4.35, p=0.02). Among 118 subjects whose mEPHX gene polymorphisms were studied, 62 (52.5%) subjects showed genotypes with slow enzyme activity while 45 (38.1%) showed normal enzyme activity and 11 (9.3%) showed fast enzyme activity. There was no significant difference in the distribution of mEPHX gene polymorphisms between the two groups. CONCLUSION: The homozygous deletion of the GSTM1 gene was associated with high lung cancer susceptibility, whereas the mEPHX genotype showed no significant connection with risk of lung cancer in a sample Korean population.
PURPOSE Small cell lung cancer is one of the major causes of death from cancer worldwide. To explore the expressions of global protein in small cell lung cancer cells, a proteomic approach, to identify the proteins, was used and the establishment of a protein reference map attempted. MATERIALS AND METHODS Two-dimensional gel electrophoresis (2-DE), with subsequent analysis by mass spectrometry (MS), was applied to the study of protein identification from a small cell lung cancer cell line, NCI- H211. The cells were lysed, and the extracts subjected to isoelectric focusing, with immobilized pH gradients, followed by second dimension SDS-PAGE. The polypeptides were identified by peptide mass fingerprinting, with MALDI-TOF MS, after in-gel protein digestion. RESULTS: From silver staining of the gel, around two thousands protein spots were separated by the 2-DE. Of these protein spots visualized in the gel, one hundred and ten were identified by peptide mass fingerprinting.
Different proteins, such as enzymes, cytoskeletal proteins and proteins common to eukaryotic cells, were identified. CONCLUSION The protein expressions of the small cell lung cancer cells were analyzed to establish a protein reference map. The reference map presented here may serve as a working tool for the further study of small cell lung cancer.
PURPOSE To evaluate the prognostic implication of histopathologic findings on the surgical specimens of N2 positive stage IIIA non-small cell lung cancer (NSCLC) patients who were treated with preoperative concurrent radiochemotherapy (CRCT) and surgery. MATERIALS AND METHODS: From May 1997 to April 2000, 48 patients with N2 positive stage IIIA NSCLC were treated with preoperative CRCT and surgery. Retrospective analyses were performed on 33 patients who underwent surgical resection. The thoracic radiation therapy (TRT) dose was 45 Gy over 5 weeks with a 1.8 Gy daily fraction using 10 MV X-rays. Chemotherapy consisted of two cycles of intravenous cisplatin (100 mg/m2, on days 1 and 29) and oral etoposide (50 mg/m2/day, on days 1~14 and 29~42), concurrently delivered with TRT. Surgery was performed around 4 weeks of the completion of CRCT. The median follow up was 18 months. The histopathologic findings, including the proportions of viable tumor cells, fibrosis, and necrosis, as well as the tumor and nodal statuses on the surgical specimens following the preoperative CRCT, were analyzed. RESULTS: The 3-year overall survival, disease-free survival, and local control rates were 46.1%, 49.5%, and 85.5%, respectively.
Post-surgical stages decreased in 18 patients (54.5%), including 3 pathologic complete responses, were unchanged in 13 (39.4%), and increased in two (6.1%). On univariate analyses, the low proportion of the viable tumor cells was the only factor favorably affecting the overall survival rate (p=0.0386), and the histologic type of squamous cell carcinoma was a favorable factor affecting disease free survival rate (p=0.0452). On multivariate analyses, however, no factor affected the overall survival, disease free survival, or local control rates. CONCLUSION: The histopathologic findings of the proportion of viable tumor cells, fibrosis, and necrosis on the surgical specimens following preoperative CRCT had few prognostic implications on uni-and multi-variate analyses. Furthermore, the primary tumor and nodal responses to preoperative CRCT did not influence the outcomes. Longer-term follow-up with a larger number of patients, however, is awaited.
Yong Tai Kim, Chul Kim, Joo Hyuk Sohn, So Young Park, Soo Young Park, Nae Choon Yu, Young Sam Kim, Se Kyu Kim, Joon Chang, Kil Dong Kim, Kyung Young Chung, Joo Hang Kim
Cancer Res Treat. 2003;35(6):502-506. Published online December 31, 2003
PURPOSE The aim of this study was to evaluate the efficacy and the safety of ZD 1839 (Iressa(R)) as a 3rd or 4th line chemotherapy regimen in NSCLC patients who are refractory to a previous chemotherapy regimen. MATERIALS AND METHODS: Twenty-five patients who were refractory to previous chemotherapy were selected for this study. The eligible patients had an ECOG performance status of 0 to 2, and an appropriate end organ function. ZD 1839 (Iressa(R))250 mg/d was orally administered until the patients experienced disease progression or unacceptable toxicity. RESULTS: Twenty-five patients were analyzed. The median age of the patients was 57 years. The response rate was 12.0% with partial responses in 3 patients. Fourteen patients (56%) remained in the stable disease state and 8 patients progressed. The median overall survival was 9.0 months (95% CI 6.7~11.2). The median progression free survival was 3 months (95% CI 2.2~3.8). Hematological toxicities of grade 3 or 4 neutropenia, anemia and thrombocytopenia were absent.
Non-hematological toxicities were grade 2 or 3 skin rashes in 10 (40.0%) patients and 1 (4.0%) patient and grade 3 nausea in 3 (12.0%) patients. No patient failed to continue chemotherapy due to any drug-related adverse events. CONCLUSION The results suggest that ZD 1839 (Iressa(R)) monotherapy is effective and tolerable as a 3rd or 4th line salvage treatment for NSCLC patients refractory to previous chemotherapy regimens.
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Serum Carcinoembryonic Antigen as an Index of the Therapeutic Effect of EGFR-TKIs in Patients with Advanced Non-Small Cell Lung Cancer Jin Hee Park, Sung Bin Kim, Sung Jin Nam, Su Hyeon Jeong, Chul Ho Oak, Tae Won Jang, Maan Hong Jung Journal of Lung Cancer.2010; 9(2): 97. CrossRef
A review of the benefit–risk profile of gefitinib in Asian patients with advanced non‐small‐cell lung cancer Keunchil Park, Koichi Goto Current Medical Research and Opinion.2006; 22(3): 561. CrossRef
PURPOSE Peritoneal seeding is the most common type of metastasis or recurrence and one of the poor prognostic factors in gastric cancer. Moreover, there are as yet no effective treatment modalities available. Recently some research groups suggested the benefit of combined cytoreductive surgery and intraperitoneal chemotherapy, but the related experiments remain in the trial stage.
Therefore, we assessed the safety and evaluated the efficacy of combined cytoreductive surgery and early postoperative intraperitoneal chemotherapy (EPIC) in gastric cancer patients with peritoneal carcinomatosis of gastric cancer. MATERIALS AND METHODS From Nov. 1997 to May. 2002, eighteen cases of combined cytoreduction and EPIC were performed in the Korea Cancer Center Hospital due to gastric cancer with peritoneal carcinomatosis. The control group consisted of 33 patients who had no resection without EPIC during the same periods. After combined cytoreductive surgery and EPIC, all patients received systemic chemotheraphy with the exception of 2 patients who could not tolerate the treatment. We retrospectively investigated the clinicopathologic features and analyzed the factors affecting the prognosis. Median follow-up period was 11.9 months (range 0.5~61 months).
Statistical analysis was performed by SPSS 11.0 for Windows.
A P-value less than 0.05 was considered as statistically significant. RESULTS: There was one case of the treatment-related mortality (5.5%) and seven cases of treatment-related complications (38%) in the combined cytoreductive surgery and intraperitoneal chemotherapy group. One-, 3- and 5-year survival rates of cytoreductive surgery plus EPIC were 57.6%, 25.9% and 13.0%, respectively, and those of the control group were 18.2%, 3% and 0%, respectively. Survival of the combined cytoreductive surgery plus EPIC group was better than that of the control group (p=0.0026). In multivariate analysis of prognostic factors affecting the survival, combined cytoreductive surgery plus EPIC (p=0.02) and systemic chemotherapy (p=0.019) were independent prognostic factors. CONCLUSION: Although a small number of cases were included in this study, combined cytoreductive surgery plus EPIC showed survival benefit and retained a comparable complication rate compared with the control group.
PURPOSE Hepatocellular carcinomas (HCC) are one of the most common cancers in Korea. The mechanism of HCC development is still unclear, and the aberration of the tumor suppressor genes in HCC remains to be clarified. MATERIALS AND METHODS: To study the expressions of p53 and Rb protein, and their correlation with the clinicopathological parameters in HCC, 68 patients, with surgically resected hepatocellular carcinomas, were analyzed by an immunohistochemical method.
The expressions of p53 and Rb protein were classified into three categorizes, depending on the percentage of stained cells. RESULTS: The expression of the p53 protein was 51.5% (35/68), and was significantly correlated with differentiation (p<0.05). The altered Rb protein expression was 72.2% (49/68). The expressions of p53 and altered Rb protein had no significant correlation with the tumor size, gender, WHO histological pattern, cirrhosis or vascular invasion (p>0.05). There was a positive correlation between p53 and Rb protein overexpression (p<0.05). The expressions of p53 and Rb protein had correlation with the Ki-67 labeling index (p<0.05). CONCLUSION: These findings suggest the aberrant expressions of p53 and Rb protein may play a role in the progression and carcinogenesis of HCC.
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Clinical significance of down-regulated HINT2 in hepatocellular carcinoma Dong-Kai Zhou, Xiao-Hui Qian, Jun Cheng, Ling-Hui Chen, Wei-Lin Wang Medicine.2019; 98(48): e17815. CrossRef
Sung Bae Kim, Myung Hwan Kim, Sung Koo Lee, Tae Won Kim, Cheolwon Suh, Jeong Sik Shin, Jung Sun Park, Eun Soon Kim, Gyungyub Gong, Jung Shin Lee, Woo Kun Kim, Sang Hee Kim
Cancer Res Treat. 2003;35(6):521-527. Published online December 31, 2003
PURPOSE Mutations in the p53 gene are reported in 50~90% of gallbladder and bile duct cancer, and have been implicated in chemoresistance. We undertook this study to determine whether the introduction of the wild type p53 gene into GBCE (human gallbladder cancer cell line with a heterozygous p53 mutation) by an adenoviral vector could increase the sensitivity of the cell to 5-FU, a commonly used drug in the treatment of gallbladder cancer. MATERIALS AND METHODS: GBCE cells were transfected with either Ad/p53 or Ad/E1 in the presence of 5-FU. Gene expression was confirmed by western blotting. Nude mice were injected subcutaneously with GBCE cells. When tumors formed, intratumoral injection of Ad/p53 was performed. Reduction of tumor size was compared in two weeks of Ad/p53 gene transfection. RESULTS: Ad/53 transfection induced a dose-dependent inhibition of tumor growth. Tumor colony formation was more inhibited with p53 gene transfection than with mock transfection in the presence of 5-FU. The reduction in tumor size was more pronounced with p53 transfection than with mock infection. CONCLUSION These treatment modalities could be utilized in the treatment of p53 mutant human gallbladder cancers.
PURPOSE The pattern of radioprotection by the combined use of low dose amifostine plus IL-1beta was investigated in mice exposed to an acute whole-body radiation dose of 10 Gy. MATERIALS AND METHODS Male ICR mice were divided into the control group, the irradiation-only group, the high dose amifostine (400 mg/kg i.p. 30 min before irradiation) group, and the low dose amifostine (200 mg/kg i.p. 30 min before irradiation) plus IL-1beta (5 microgram/kg i.p. 20 h before irradiation) group. The radioprotective effects were evaluated using TUNEL assay and microcolony survival assay at jejunal crypt, bone marrow cell count and CBC in peripheral blood, and survival analysis up to 30 days following irradiation. RESULTS: The apoptotic index (p=0.987), surviving crypt number (p=0.484), and the number of WBCs (p=0.226), RBCs (p=0.544), and platelets (p=0.157) were not significantly different between the high dose amifostine group and the low dose amifostine plus IL-1beta group, although the bone marrow cell count was higher in the combination group. The irradiation-only group was dead within 15 days. However, the survival rate at 30 days in the high dose amifostine and the low dose amifostine plus IL-1beta pretreatments were 61% and 66%, respectively.
Moreover, the differences between the two groups were insignificant for both 10 days (p=0.9461) and 30 days (p=0.8030). CONCLUSION: These results indicate that the low dose amifostine plus IL-1beta may be applied as a non-toxic radioprotector, while the high dose amifostine, known as the strongest radioprotector, however, had toxic side effects.
PURPOSE The cDNA microarray has become a useful tool for observing the expression of thousands of genes simultaneously. However, obtaining good quality microarray data is not easy due to the inherent noise at various stages of the experiment. Therefore, it is essential to understand the source of the variation in the microarray experiment and its size as an initial step of the data analyses. MATERIALS AND METHODS: The total RNA extracted from HT-1080 fibrosarcoma and normal rat tissues were hybridized to the cDNA microarrays with 0.5 K human and 5 K rat genes, respectively. A homotypic reaction and dye swap experiments were used to identify the sources of the variation. RESULTS: The relative fluorescent intensities of the microarray, if unnormalized, have a large variation, particularly in the lower intensity region. The distribution of the log intensity ratios also exhibit some departure from a band around zero, which is the distribution pattern expected when the majority of genes in the microarray are not regulated.
Normalization of the log ratios is usually required as a means of preprocessing the data. We claim that a within-print tip group, an intensity-dependent normalization through a loess fit adjustment will be useful for this purpose, particularly in the initial stages of the microarray experiment. CONCLUSION: For proper data analysis, an understanding the source of the variation and preprocessing of data with a suitable normalization method will be important. It is important to have an interactive cooperation between a researcher and a statistician from the early stages of the study design and to the final stages of data analysis.
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Whole genome analysis for liver metastasis gene signatures in colorectal cancer Dong Hyuk Ki, Hei‐Cheul Jeung, Chan Hee Park, Seung Hee Kang, Gui Youn Lee, Won Suk Lee, Nam Kyu Kim, Hyun Chul Chung, Sun Young Rha International Journal of Cancer.2007; 121(9): 2005. CrossRef
PURPOSE Speculoscopy, or magnified chemiluminescent examination (MCE), is a new visual method for the detection of cervical neoplasia. It utilizes low magnification and a special "blue-white" chemiluminescent light. The purpose of this study was to evaluate the screening effectiveness of speculoscopy combined with the conventional Papanicolaou smear, as compared with the latter alone, through a clinical trial in Korea. MATERIALS AND METHODS: This prospective, randomized, university hospital-based clinical study was performed in the outpatient clinic of the Department of Obstetrics and Gynecology at Dankook University Medical Center from December 1, 2001 to June 30, 2002. Of the 113 patients aged 19~74 years who had undergone both conventional Papanicolaou cervical cytologic test and speculoscopy, 38 cases underwent histologic diagnoses by colposcopy- directed biopsy. RESULTS: Of the 113 patients, there were 87 (77.0%) spe-culoscopy diagnoses of negative, 9 (8.0%) of suspicious, and 17 (15.0%) of positive. Of the 38 histologic diagnoses, there were 19 (50.0%) diagnoses of negative, 7 (18.4%) of LSIL, 1 (2.6%) of HSIL, 10 (26.3%) of SCC, and 1 (2.6%) of ACC. Pap smear showed sensitivity of 77.8% and specificity of 81.3%, whereas speculoscopy showed 94.1% and 100.0%, respectively, and Pap smear combined with speculoscopy showed 100.0% and 81.3%, respectively. CONCLUSION Speculoscopy showed a higher sensitivity rate than Pap smear as a screening test, although the sample size was small. Speculoscopy combined with Pap smear is thought to be a very effective method for detecting cervical neoplasia.
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Looking Beyond VIA to Improve Cervical Cancer Screening in Low Resource Settings Bharti Goel, Argyia Desouza, Alka Sehgal, Sunita Dubey The Journal of Obstetrics and Gynecology of India.2022; 72(6): 503. CrossRef
Su Mi Bae, Seung Won Huh, Eun Kyung Park, Keun Ho Lee, Joon Mo Lee, Sung Eun Namkoong, Sei Jun Han, Chong Kook Kim, Jong Ki Kim, Yong Wan Kim, Woong Shick Ahn
Cancer Res Treat. 2003;35(6):549-556. Published online December 31, 2003
PURPOSE In order to elucidate the antitumor effect of photodynamic therapy (PDT), using a derivative of the photosensitizing agent hematoporphyrin (Photogem) and a diode laser, the cell death of uterine cancer cell lines (CaSki, HT3, HeLa, and SKOV-3), and mice transplanted with TC-1 lung cancer cells, were evaluated. MATERIALS AND METHODS: The morphological changes, MTT assay, flow cytometry, cytotoxicity and tumor growth inhibition study were evaluated at various time intervals after the PDT. RESULTS The results showed that the survival rates of each cell line decreased with time and dose response after performing the PDT. Also, the PDT-induced damage of cancer cells was almost entirely confined to necrosis of the tumor cells in the early time courses. The irradiation of CaSki cells in the presence of Photogem induced plasma membrane disruption and cell shrinkage, indicating the plasma membrane as the main target for Photogem. In the in vivo experiment, significantly longer survival and a significantly smaller tumor size were seen over the time courses of the Photogem with irradiation compared to the untreated control groups; resorption of the tumor was also observed after the PDT treatment. CONCLUSION: Collectively, our results indicated that Photogem possesses anti-tumor effects, and necrosis-like death, with plasma membrane damage, was postulated to be the principal mechanism of the antitumor effect of the PDT using Photogem.
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Shift from Apoptotic to Necrotic Cell Death during Human Papillomavirus-induced Transformation of Keratinocytes Nataly Kravchenko-Balasha, Sarit Mizrachy-Schwartz, Shoshana Klein, Alexander Levitzki Journal of Biological Chemistry.2009; 284(17): 11717. CrossRef
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