• Title/Summary/Keyword: p-gp

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Triplet Platinum-based Combination Sequential Chemotherapy Improves Survival Outcome and Quality of Life of Advanced Non-small Cell Lung Cancer Patients

  • Chen, Li-Kun;Liang, Ying;Yang, Qun-Ying;Xu, Fei;Zhou, Ning-Ning;Xu, Guang-Chuan;Liu, Guo-Zhen;Wei, Wei-Dong
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.5
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    • pp.1863-1867
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    • 2012
  • Background: Maintenance chemotherapy is one strategy pursued in recent years with intent to break through the chemotherapy plateau for advanced non-small cell lung cancer (NSCLC). However, given the toxicity, platinum-based combinations are rarely given for this purpose. We carried out the present prospective study of triplet platinum-based combination sequential chemotherapy in advanced NSCLC to investigate if patients could tolerate and benefit from such intensive treatment. Methods: From Dec 2003 to Dec 2007, 190 stage IIIB and IV NSCLC patients in Sun yat-sen University sequentially received the 3 platinum-based combination (TP-NP-GP) treatment (T: paclitaxol175$mg/m^2$ d1; N: vinorelbine25$mg/m^2$ d1 and 8; G: gemcitabine1$g/m^2$ d1 and 8; P: cisplatin20$mg/m^2$ d1-5; repeated every 3 weeks). Patients were followed up to at least 3 years to obtain survival data. Treatment toxicities and the quality of life (QOL) were assessed during the whole treatment. Results: There were 187 patients evaluable. The TP, NP and GP response rates with sequential use were 42.8% (80/187), 41.1% (65/158) and 28.8% (21/73) respectively. Median survival time was 18.2 months and the 1, 2 and 3 year overall survival (OS) rates were 78.7%, 38.5% and 21.3%. Patients receiving > 6 cycles of chemotherapy had significantly longer OS and TTP (MST 25.3 vs. 14.5 months, TTP 15.1 vs. 9.1 months). The QOL on the whole for the patients was improved after chemotherapy. Conclusions: The sequential chemotherapy strategy with triplet platinum-based combination regimens can improve the survival outcome and the quality of life of advanced non-small cell lung cancer patients.

Characterization and Resistance Mechanisms of A 5-fluorouracil-resistant Hepatocellular Carcinoma Cell Line

  • Gu, Wei;Fang, Fan-Fu;Li, Bai;Cheng, Bin-Bin;Ling, Chang-Quan
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.9
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    • pp.4807-4814
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    • 2012
  • Purpose: The chemoresistance of human hepatocellular carcinoma (HCC) to cytotoxic drugs, especially intrinsic or acquired multidrug resistance (MDR), still remains a major challenge in the management of HCC. In the present study, possible mechanisms involved in MDR of HCC were identified using a 5-fluorouracil (5-FU)-resistant human HCC cell line. Methods: BEL-7402/5-FU cells were established through continuous culturing parental BEL-7402 cells, imitating the pattern of chemotherapy clinically. Growth curves and chemosensitivity to cytotoxic drugs were determined by MTT assay. Doubling times, colony formation and adherence rates were calculated after cell counting. Morphological alteration, karyotype morphology, and untrastructure were assessed under optical and electron microscopes. The distribution in the cell cycle and drug efflux pump activity were measured by flow cytometry. Furthermore, expression of potential genes involved in MDR of BEL-7402/5-FU cells were detected by immunocytochemistry. Results: Compared to its parental cells, BEL-7402/5-FU cells had a prolonged doubling time, a lower mitotic index, colony efficiency and adhesive ability, and a decreased drug efflux pump activity. The resistant cells tended to grow in clusters and apparent changes of ultrastructures occurred. BEL-7402/5-FU cells presented with an increased proportion in S and G2/M phases with a concomitant decrease in G0/G1 phase. The MDR phenotype of BEL-7402/5-FU might be partly attributed to increased drug efflux pump activity via multidrug resistance protein 1 (MRP1), overexpression of thymidylate synthase (TS), resistance to apoptosis by augmentation of the Bcl-xl/Bax ratio, and intracellular adhesion medicated by E-cadherin (E-cad). P-glycoprotein (P-gp) might play a limited role in the MDR of BEL-7402/5-FU. Conclusion: Increased activity or expression of MRP1, Bcl-xl, TS, and E-cad appear to be involved in the MDR mechanism of BEL-7402/5-FU.

A Traffic Simulation Model Verification Method Using GPS Equipment (GPS를 활용한 교통 시뮬레이션 모형 검증)

  • Hu, Hyejung;Baek, Jongdae;Han, Sangjin
    • The Journal of The Korea Institute of Intelligent Transport Systems
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    • v.11 no.5
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    • pp.62-69
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    • 2012
  • Traffic simulation models have been used for assessing various transportation strategies. Through comparing results from a simulation model and real field data, researchers try to show how close the model can reproduce the real world traffic. This model verification step is one of the most essential tasks in modeling procedure. Traffic counts and speeds have been frequently used for the verification or validation. Authors modeled severe PM peak bottleneck situation on the I-40 corridor in Raleigh, North Carolina using DYNASMART-P, a mesoscopic traffic simulation tool and verified the model. NCDOT has Traffic Information Management System which has archive capability for the traffic speeds on the I-40 corridor. However, the authors selected travel time as the field measure for model verification and collected the data using a GPS equipment because the speed data from NCDOT speed detectors are spot speeds which are not appropriate for comparison with link average speed from the simulation model. This paper describes the GPS field data collection procedure, the model verification method, and the results.

Comparative Research on the Vegetation and Changes of Microclimate on the Fire Damaged and Undamaged Areas (산림피해림지와 무피해림지의 식생과 미기상변화에 관하여)

  • Kim, Woen;Chong Un Ri;Uen Ho Lee
    • The Korean Journal of Ecology
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    • v.4 no.3_4
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    • pp.109-113
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    • 1981
  • The area damaged by the fire effect, most serious artificial damage of forest, was measured to analysis vegetation structures and changes of microclimate at the region of the Pal-gong mountain. Vegetation of whole investigated area was Querceto-Pinetum with rich differetial species. But at the areas fire damaged and undamaged, few differential were noted. The two communites appear physiognomical different of temperature according to height an ddepth at the area of damaged was 11:00 a.m. and 13:00 p.m. at undamaged area. On the whole, high temperature distribution at the damaged area and sensitive reaction by the changes of solar radiation were noticed. Changes of humidity according to height were few, but the saturating deficient at 13:00 p.m. at the whole investigated area extremely high and sensitive at the damaged area.

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Grid-based Cloaking Area Creation Scheme supporting Continuous Query Processing for Location-based Services of Peer-to-Peer Environment (P2P 환경의 위치 기반 서비스에서 연속적인 질의 처리를 지원하는 그리드 기반 Cloaking 영역 설정 기법)

  • Kim, Hyeong-Il;Lee, Ah-Reum;Chang, Jae-Woo
    • Spatial Information Research
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    • v.18 no.3
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    • pp.53-62
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    • 2010
  • Recent development in wireless communication technology, like GPS, and mobile equipments, like PDA and cellular phone, make location-based services (LBSs) popular. However, because, users continuously request a query to a server in the LBSs by using their exact locations, privacy information could be in danger. Therefore, a mechanism for users' privacy protection is required for the safe and comfortable use of LBSs by mobile users. For this, we, in this paper, propose a grid-based cloaking area creation scheme supporting continuous LBSs in peer-to-peer environment. The proposed scheme creates a cloaking area by using Chord protocol, so as to support the continuous LBSs in peer-to-peer environment. Finally, we show from a performance analysis that our cloaking scheme outperforms the existing cloaking schemes, in terms of service time.

Role of Caveolin-1 in Indomethacin-induced Death of Human Hepato-adenocarcinoma SK-Hep1 Cells

  • Kim, Kyung-Nam;Kang, Ju-Hee;Yim, Sung-Vin;Park, Chang-Shin
    • The Korean Journal of Physiology and Pharmacology
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    • v.12 no.4
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    • pp.143-148
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    • 2008
  • Caveolin-1 (CAV1) is an integral membrane protein that may function as a scaffold for plasma membrane proteins and acts as a tumor suppressor protein. One causative factor of chemotherapy-resistant cancers is P-plycoprotein (P-gp), the product of the multidrug resistance-1 gene (MDR1), which is localized in the caveolar structure. Currently, the interactive roles of CAV1 and MDR1 expression in the death of cancer cells remain controversial. In this study, we investigated the effects of indomethacin on the cell viability and the expression levels of MDR1 mRNA and protein in a CAV1-siRNA-mediated gene knockdown hepatoma cell line (SK-Hep1). Cell viability was significantly decreased in CAV1-siRNA-transfected cells compared with that of control-siRNA-transfected cells. Furthermore, the viability of cells pretreated with CAV1 siRNA was markedly decreased by treatment with indomethacin (400${\mu}$M for 24 h). However, the protein and mRNA levels of MDR1 were unchanged in CAV1-siRNA-transfected cells. These results suggest that CAV1 plays an important role as a major survival enzyme in cancer cells, and indomethacin can sensitively induce cell death under conditions of reduced CAV1 expression, independent of MDR1 expression.

Human Papillomavirus Genotypes and Cervical Cancer in Northeast Thailand

  • Natphopsuk, Sitakan;Settheetham-Ishida, Wannapa;Pientong, Chamsai;Sinawat, Supat;Yuenyao, Pissamai;Ishida, Takafumi;Settheetham, Dariwan
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.11
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    • pp.6961-6964
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    • 2013
  • Human papillomavirus (HPV) is a major cause of cervical cancer. More than 100 HPV genotypes have been identified; however the distribution varies geographically and according to ethnicity. The purpose of this study was to investigate the prevalence and distribution of HPV subtypes among Northeast Thai women. Subjects included 198 cases of SCCA and 198 age-matched, healthy controls. HPV-DNA was amplified by PCR using the consensus primers GP5+/6+ system followed by reverse line blot hybridization genotyping. The prevalence of high-risk HPV infection was 21 (10.1%) and 152 (76.8%) in the controls and in the cases, respectively. High-risk HPV significantly increased the risk for cervical cancer with an OR of 42.4 (95%CI: 22.4-81.4, p<0.001) and an adjusted OR of 40.7-fold (95%CI: 21.5-76.8, p <0.001). HPV-16 was the most prevalent HPV type in the SCCA (56.2%) followed by HPV-58 (17.8%) and HPV-18 (13.6%); whereas HPV-58 (46.4%) was a prominent genotype in the controls followed by HPV-16 (39.3%) and unidentified HPV types (25.0%). These findings indicate that HPV infection remains a critical risk factor for SCCA; particularly, HPV-16, HPV-58 and HPV-18. In order to eradicate cervical cancer, sustained health education, promoted use of prophylactics and a HPV-58 vaccine should be introduced in this region.

Lack of Association of the MDR1 C3435T Polymorphism with Susceptibility to Gastric Cancer and Peptic Ulcer: a Systemic Review and Meta-analysis

  • Wu, Dan-Dan;Zhang, Ji-Xiang;Li, Jiao;Dong, Wei-Guo
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.7
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    • pp.3021-3027
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    • 2014
  • Background: The multidrug resistance 1 gene (MDR1) C3435T polymorphism has been demonstrated to influence the P-glycoprotein (P-gp) activity level which is related to inflammation and carcinogenesis. This meta-analysis was performed to estimate the association between the MDR1 C3435T polymorphism and the risk of gastric cancer (GC) and peptic ulcer (PU). Materials and Methods: A literature search was conducted with PubMed, Embase and the Cochrane library up to November 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Data were analyzed using Review Manager (Version 5.2), and Stata package (version 12.0) for estimation of publication bias. Results: Six case-control studies were included, of which five were for GC and two for PU. Overall, no evidence was found for any association between the MDR1 C3435T polymorphism and the susceptibility to GC and PU. In the stratified analysis by H. pylori infection status, stage and histology classification of GC, and PU type, there was still no significant association between them. Conclusions: This meta-analysis suggested that the MDR1 C3435T polymorphism is not associated with susceptibility to GC and PU. Large and well-designed studies are warranted to validate our findings.

In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

  • Ahn, Sung-Hoon;Heo, Tae-Hwe;Jun, Hyun-Sik;Choi, Yongseok
    • Asian-Australasian Journal of Animal Sciences
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    • v.33 no.4
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    • pp.670-677
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    • 2020
  • Objective: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, in vitro liver microsomal stability and an in vivo pharmacokinetic study using BALB/c mice were characterized. Methods: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and in vitro pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For in vivo pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated. Results: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (Papp; 9.7×10-6 cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t1/2) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 μM. The area under the plasma drug concentration-time curve and Cmax after oral administration (5 mg/kg) of LMT-28 were 302±209 h·ng/mL and 137±100 ng/mL, respectively. Conclusion: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

Flight behavior of cinereous vultures (Aegypius monachus) in the wintering season in Korea (한국에 월동하는 독수리의 비행 행동 특성 분석)

  • Kang, Tehan;Lee, Sangbo;Lee, Hansoo;Peak, Woon-Kee;Yu, Jae Pyoung;Jin, Seon-Deok
    • Korean Journal of Environmental Biology
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    • v.37 no.4
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    • pp.579-584
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    • 2019
  • The flight characteristics of 11 cinereous vultures (Aegypius monachus) were analyzed by a global positioning system (GPS) tracker(WT-300; KoEco, Inc.). The wintering period in Korea averaged 131 days (SD=17.4) and the average flight rate was 19.6%. The flight altitude was below 100 m for 21.6% of the flight, 101-200 m for 25.3%, 201-300 m for 19.0%, and below 300 m for 65.9%. There was a positive correlation (r=0.929) between the hourly flight rate and altitude. The predominant monthly flight altitude was 101-200 m (p<0.05). The wintering cinereous vultures lowered their flight rate and flew at an altitude of less than 300 m. This is thought to be an efficient way to find food through social interaction.