• Biomolecules & Therapeutics
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• 제27권6호
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• pp.530-539
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• 2019

Brain aging is an inevitable process characterized by structural and functional changes and is a major risk factor for neurodegenerative diseases. Most brain aging studies are focused on neurons and less on astrocytes which are the most abundant cells in the brain known to be in charge of various functions including the maintenance of brain physical formation, ion homeostasis, and secretion of various extracellular matrix proteins. Altered mitochondrial dynamics, defective mitophagy or mitochondrial damages are causative factors of mitochondrial dysfunction, which is linked to age-related disorders. Etoposide is an anti-cancer reagent which can induce DNA stress and cellular senescence of cancer cell lines. In this study, we investigated whether etoposide induces senescence and functional alterations in cultured rat astrocytes. Senescence-associated ${\beta}$-galactosidase (SA-${\beta}$-gal) activity was used as a cellular senescence marker. The results indicated that etoposide-treated astrocytes showed cellular senescence phenotypes including increased SA-${\beta}$-gal-positive cells number, increased nuclear size and increased senescence-associated secretory phenotypes (SASP) such as IL-6. We also observed a decreased expression of cell cycle markers, including PhosphoHistone H3/Histone H3 and CDK2, and dysregulation of cellular functions based on wound-healing, neuronal protection, and phagocytosis assays. Finally, mitochondrial dysfunction was noted through the determination of mitochondrial membrane potential using tetramethylrhodamine methyl ester (TMRM) and the measurement of mitochondrial oxygen consumption rate (OCR). These data suggest that etoposide can induce cellular senescence and mitochondrial dysfunction in astrocytes which may have implications in brain aging and neurodegenerative conditions.

• Tuberculosis and Respiratory Diseases
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• 제52권4호
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• pp.309-316
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• 2002

연구배경: 비소세포 폐암은 전체 폐암의 75-85%를 차지하며 근치적 절제술이 완치를 기대할 수 있는 치료 방법이나 진단 당시 대부분 절제 불가능한 상태로 10-35% 정도만이 수술이 가능하므로 많은 환자에게서 방사선 치료와 항암 화학요법이 시도되고 있다. 이에 본 연구자들은 진행성 비소세포성 폐암 환자들에게 ICE 복합 화학요법을 적용하여 치료 효과와 부작용 등을 조사하였다. 방 법: 1995년 3월부터 1996년 12월까지 조직학적으로 비소세포성 폐암으로 진단받고 진행성 혹은 전이성 병변 등으로 인해 수술이 불가능한 한자중 과거 항암 화학요법이나 방사선 치료를 받지 않은 환자를 대상을 하여 ICE 복합화학요법(Ifosfamide $1.5mg/m^2$ full drop with Mesna day 1-5, Cisplatin $80mg/m^2/day$ infusion with hydration day 2, Etoposide infusion for 2 hours day 1-3)을 4주 간격으로 시행하였다. 결 과: 전체 33명의 환자 중 완전 관해는 없었으며, 부분 관해는 10명(30.3%)이었다. 반응군이 무반응군에 비해 통계적으로 유의한(p=0.01) 생존율의 향상을 보였고 전체 33명의 전체 생존기간은 $35.30{\pm}4.36$주로 관찰되었다. 부작용은 수용할만 한 것으로 관찰되었고 Grade 3-4이상의 중요한 혈액학적 부작용으로는 호중구 감소증이 21%에서 관찰되었다. 환자에게 투여된 약제의 상대적 수용용량강도는 ifosfamide가 0.86, cisplatin이 0.87, etoposide가 0.89로 평균적으로 0.87의 용량강도가 주입되었다. 결 론: 이상의 결과로 Ifosfamide, Cisplatin, Etoposide(ICE) 복합화학요법은 부작용은 수용할만하면서 기존의 복합항암치료와 유사한 반응률을 보여 진행성 비소폐암이 한 치료 방법으로 생각된다.

• Tuberculosis and Respiratory Diseases
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• 제48권5호
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• pp.740-747
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• 2000

연구배경 : 저자들은 전신병기 소세포 폐암 환자중 VPP/CAV 교대요법을 받은 환자군과 CE요법을 받은 환자군에 대하여 치료반응과 생존기간 그리고 부작용 등을 평가 하여 전신 병기 소세포 폐암 환자의 초치료로 CE요법이 유용한가에 대하여 알아보고자 하였다. 방법 : VPP/CAV교대요법을 받은 환자들은 cisplatin 60mg/$m^2$를 제 1일에 정주하였고 etoposide 100mg/$m^2$를 제 1일에서 제 3일까지 정주한 후, 3주 후에 다시 cyclophosphamide 1000mg/$m^2$, adriamycin 40mg/$m^2$, vincristine 1.4mg/$m^2$를 정주하였고 매 3주마다 반복하였다. CE요법을 받은 환자들은 carboplatin 325mg/$m^2$를 제 1일에 정주하였고, etoposide 100mg/$m^2$를 제 1일에서 제 3일까지 정주하여 매 3주마다 반복하였다. 양군 모두에서 필요한 경우에는 고식척인 방사선 시행하였다. 결과 : 전체 반응률은 61.4% 이었고 중앙 생존기간은 10.8개월이었다. VPP/CAV교대요법군의 경우 반응률은 54.5%, 중앙 생존기간은 9.5개월이었고, CE요법군의 경우 반응률은 68.2%, 중앙 생존기간은 11개월이었으나 양군간에 통계학적인 차이는 없었으며 부작용은 비슷하였으나, CE요법 군에서 빈혈이 더 많았다. 결론 : CE요법은 VPP/CAV교대요법과 동등한 반응률을 보였으며 부작용도 수용할만하여 전신병기 소세포 폐암환자들에서 초치료 약제로 적절한 것으로 판단된다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2467-2471
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• 2012

Introduction: Although bleomycin/etoposide/cisplatinum (BEP) chemotherapy is established as the standard treatment for germ cell tumours, it requires significant experience in administration and toxicity management to maintain optimal dose intensity. A retrospective review of 30 patients was conducted at UKMMC to study treatment outcomes. Methods & Materials: Patients with GCTs and treated with at least two cycles of BEP chemotherapy between January 2003 and Oct 2009 were eligible for this study. Patients received 4-6 cycles of bleomycin 30,000IU IV D1, D8 & D15 and either etoposide $100mg/m^2$ IV D1-D5 and cisplatin $20mg/m^2$ IV D1-D5 (5 day BEP regimen) or etoposide $165mg/m^2$ D1-D3 and cisplatin $50mg/m^2$ D1-3 (3 day BEP regimen) every three weeks per cycle. All patients received prophylactic granulocyte colony-stimulating factor (GCSF) from days 6 to 10 of each cycle. The overall response rates, 2 year progression-free survival and overall survival of the whole cohort were assessed. Results: Thirty patients fulfilled the inclusion criteria. Non-seminomatous GCTs comprised 93.3% of cases and gonadal and mediastinal primary sites were the most common. Sixty percent were classified as IGCCCG poor risk disease. Median follow-up was 26.6 months. The overall response rate (CR+PR) was 70%. The two year PFS and OS were 70% and 66%. There was a significant difference in terms of the overall response rate (85% vs 40%, p = 0.03) and in PFS (94.7% vs 50%, p = 0.003) between gonadal and extragonadal primary sites. Conclusion: It is possible to achieve outcomes similar to those in international clinical trials with close monitoring and good supportive care of patients undergoing BEP chemotherapy. There is a strong argument for patients with IGCCCG poor prognosis disease to be treated in specialist tertiary centres to optimize treatment outcomes.

• 한국식품과학회지
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• 제34권1호
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• pp.114-117
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• 2002

연교의 메탄올 추출물로부터 caspase 저해물질을 분리하였으며, ESI-MS, $^1H-NMR$, $^13C-NMR$, DEPT 등의 기기분석 자료에 의하여 rengyolone으로 동정하였다. 이 물질은 $IC_{50}\;6.25\;{\mu}g/mL$의 농도에서 etoposide가 처리된 U937 세포주의 caspase-3 유도 저해를 나타내었다. 또한 rengyolone은 $Interleukin-1{\beta}$가 처리된 D10S 세포에서 caspase-1의 유도저해활성을 나타내었으며, $IC_{50}$값은 $7.5\;{\mu}g/mL$이었다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권20호
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• pp.8843-8846
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• 2014

Background: Malignant mesothelioma (MM) is almost always fatal and few treatment options are available. The aim of this study was to evaluate the efficacy of oral cyclophosphamide and etoposide for patients who underwent standard treatment for advanced MM. Materials and Methods: This study included 22 malignant pleural mesothelioma patients who were treated with oral cyclophosphamide and etoposide (EE). Results: The average follow-up period of the patients was 39.1 months. Under the treatment of oral EE, median progression-free survival was 7.7 months [95%CI HR (4.3-11.1)] and median overall survival was 28.1 months [95%CI HR (5.8-50.3)]. The treatment response rates were as follows: 4 patients (27.3%) had a partial response (PR), 12 (54.5%) had stable disease (SD), and progressive disease (PD) was observed in 6 (35.9%). Conclusions: Oral EE can be administered effectively to patients with inoperable malignant mesothelioma who had previously received standard treatments.

• Journal of Gastric Cancer
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• 제3권3호
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• pp.122-127
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• 2003

Purpose: The incidence rate and the mortality rate of gastric cancer have decreased in developed countries over the last several decades. On the other hand, they remain high in far eastern countries such as Korea, Japan, China and in many developing countries. The cure of patients with gastric carcinomas can be achieved mostly through complete surgical resection, but most gastric cancer patients are in advanced stages when diagnosed and have poor prognoses. therefore, the development of an effective systemic therapy is essential for far advanced gastric cancer patients. Until recently, the most commonly used combination chemotherapy was based on 5-flurouracil or cisplatin, but the results were not satisfactory, so recently etoposide, adriamycin and cisplatin (EAP-II) combination chemotherapy was introduced in patients with advanced gastric cancer. Early studies showed a high response rate and the ability to convert unresectable cases to resectable ones, but later studies couldn't duplicate the result. the purpose of this study was to evaluate the relative efficacy & toxicity of EAP-II chemotherapy and ELF chemotherapy which is based on 5-flurouracil. Materials and Methods: Between July 1992 and July 2002, sixty-five patients with inoperable advanced gastric cancer were enrolled for this study. Thirty-seven patient received EAP-II chemotherapy:etoposide (20 mg/$m^{2}$ IV for $1\∼5 days$), adriamycin (20 mg/$m^{2}$ IV for $1\∼5 days$) and cisplatin (20 mg/$m^{2}$ IV for $1\∼5 days$) and Twenty-eight patients receieved ELF chemotherapy : etoposide (100 mg/$m^{2}$ IV for $1\∼3 days$), leucovorin (20 mg/$m^{2}$ IV for $1\∼5 days$) and 5-FU (500 mg/$m^{2}$ IV for $1\∼5 days$). Each treatment schedule for each group was repeated every four weeks: EAP-II means 3.4 cycles per patient..ELF means 4.1 cycles per patient Results: Total respones rates were $5.4\%$ in the ELF group and $3.6\%$ in the EAP group (P-value>0.05). The median times to progression were 144 days in the ELF group and 92 days in the EAP-II group (P-value<0.05), and themedian overall survival times were 189 days in the ELF group and 139 days in the EAP-II group (P-value>0.05). The difference in the survival curves for the two regimens was not statistically significant. Non-hematologic toxicitis & hematologic toxicitis were more frequently observed for the EAP-II regimen. Anemia: $27.6\%$ in ELF vs $54\%$ in EAP-II; Leukopenia: $8.5\%$ in ELF vs $19\%$ in EAP-II; nausea & vomiting: $45.9\%$ in ELF vs $67.8\%$ in EAP-II. Conclusion: EAP-II regimen is not superior to ELF regimen in the tratment of inoperable advanced gastric cancer (J Korean Gastric Cancer Assoc 2003;3:122-127)

• Tuberculosis and Respiratory Diseases
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• 제41권6호
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• pp.632-643
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• 1994

연구배경: 소세포폐암은 빠른 증식속도와 조기에 전신전이를 나타내지만 화학요법에 비교적 반응을 잘한다고 알려져 있다. 최근 10년간 CAV에 실패한 환자의 이차 치료로서 사용되던 cisplatin과 etoposide 복합 화학요법(PVP)을 소세포 폐암 환자에서 일차 치료로서 시행하여 높은 반응률을 보고하고 있다. 이에 저자등은 PVP요법의 유효성 및 안정성을 평가하고자 하였다. 방법: 1989년 11월부터 1991년 12월까지 원자력 병원에서 소세포 폐암으로 진단받은 61명의 환자들을 대상으로 cisplatin $30mg/m^2$와 etoposide $100mg/m^2$을 제1일부터 제3일까지 정주하고 매 3주 간격으로 반복 치료하여 그 결과를 판정 하였다. 결과: 총 61명의 환자중 평가가 가능한 55명에서 완전반응이 13예(24%), 부분반응이 29예(53%), 불변이 9예(16%), 진행이 4예(7%)로 총반응률은 77% 였다. 제한기에서는 완전반응이 8예(26%), 부분반응이 21예(68%)였고 확대기에서는 완전반응이 5예(21%), 부분반응이 8예(33%)였으며, 전체 생존기간의 중앙치가 55.8주, 제한기가 61.1주, 확대기가 51.3주였다. 그리고 전체 반응군의 반응유지기간은 29.1주였고 심각한 부작용은 없었다. 결론: 소세포 폐암에 있어서 PVP요법은 일차치료로 사용시 심각한 부작용이 없으면서 비교적 효과적인 복합 화학요법으로 생각된다.

• Molecules and Cells
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• 제21권3호
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• pp.395-400
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• 2006

Glutathione S-transferase P1 (GSTP1) plays an important role in detoxification and the metabolism of xenobiotics. Here we show that GSTP1 also regulates the MEKK1-MKK7 signaling pathway. Over-expression of GSTP1 in HEK293 cells inhibited both ${\Delta}MEKK1$- and etoposide-induced apoptosis, and inhibited procaspase-3 activation and PARP cleavage. MEKK1- induced apoptosis requires both its kinase activity and proteolytic cleavage. ${\Delta}MEKK1$ activity was inhibited by over-expression of GSTP1 in vivo and MEKK1 kinase activity was also inhibited by GSTP1 in vitro when assayed with bacterially-expressed MKK7(KM) protein as substrate. GSTP1 inhibition of etoposide-induced cell apoptosis was mainly due to its ability to suppress MEKK1 kinase activity. The glutathione-conjugating activity of GSTP1 was essential for the above effects. These findings provide insight into the mechanism by which GSTP1 protects cells from genotoxin-induced apoptosis.

• IMMUNE NETWORK
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• 제1권3호
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• pp.221-229
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• 2001

Background: Inactivation of tumor suppressor genes is believed to be important in the development of many human malignancies. Recently, several lines of evidence have indicated that the wild type p53 gene located at 17p13.3, may function as a tumor suppressor gene and that a mutant p53 gene could promote transformation by inactivating normal p53 function in a dominant negative fashion. These broad spectrum of p53 mutation in human cancers provide that mutant p53 and their protein may be potential targets of tumor diagnostic and therapeutic interventions. Method: Colony formation was performed to investigate growth suppressional ability. p53 expression pattern was examined by western blot and p53-mediated transactivation ability was assessed by CAT activity. SNU C2A cells were observed in apoptotic aspects induced by etoposide and $H_2O_2$ treatment, detecting sensitivity on agent, DNA fragmentation through agarose gel, chromatin condensation by fluorescence microscope, and cell cycle distribution by FACS. Result: 1) p53 mutant his179arg ($histidine{\rightarrow}arginine$) detected in SNU C2A cells lost transcriptional activity and growth suppression ability, showing dominant negative effect on its wild type p53. 2) Etoposide-treated SNU C2A cells induced apoptosis, exhibiting dramatic reduction of cell growth, DNA fragmentation, nuclear condensation formation of apoptotic body and increment of sub-G1 cell fraction. 3) Etoposide and $H_2O_2$-treated SNU C2A cells have no high increase of p53 expression and overexpressed p53 protein changed localization, from cytoplasm to nucleus. Also, p53-mediated transcriptional activity was increased by agents-treatment. Conclusion: SNU C2A cells coexpress wild-type and mutant p53 protein induced apoptosis in the condition on DNA damage, through localizational shift from cytoplasm to nucleus of p53 protein rather than the induction of p53 protein. SNU C2A cells derived mutant p53 his179arg abrogated both the growth supression ability and transactivational activity, showing inhibition effect on transcriptional activity of wild type p53, but did not repress the activity of wild type p53 in SNU C2A cells owing to dominant activity of wild type. These cell condition may provide new gene therapeutic implications leading effective antiproliferation of cell when mutant and wild-type p53 protein were co-expressed in cell.