(3.80.6.131) 您好!臺灣時間:2021/05/17 01:26
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:林萍平
研究生(外文):Ping-Ping Jernie Lim
論文名稱:化療藥物Ara-C抗藥性細胞株MV-4-11-R的建立及其特性研究
論文名稱(外文):Establishment & Characterization of cytarabine resistant cell lines-MV-4-11-R
指導教授:林亮音
指導教授(外文):Liang-In Lin
口試委員:胡忠怡郭遠燁歐大諒顧雅真
口試日期:2013-06-26
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:100
中文關鍵詞:急性骨髓性白血病Ara-CMV-4-11
外文關鍵詞:Acute myeloid leukemiaAra-CMV-4-11
相關次數:
  • 被引用被引用:0
  • 點閱點閱:411
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
Ara-C 是治療AML常用的藥物,大部分病人可以獲得良效,但仍有部分患者病情不能緩解或緩解後復發。目前認為導致病患復發的主要原因是患者對化療藥物產生抗藥性。已知的抗藥機制繁多,但目前為止還不足以解釋Ara-C產生抗藥性的原因。為了更了解Ara-C的抗藥性機制,本實驗室建立出對Ara-C有抗藥性的MV-4-11 AML細胞株(MV-4-11-R),再以細胞抑殺實驗檢測Ara-C對MV-4-11-R細胞株之生長抑制情形,結果顯示其IC50為3.37μM,與母細胞MV-4-11-P (IC50為0.26 μM)相差13倍。對這兩株細胞進行一系列的生物特性分析。結果發現MV-4-11-P和MV-4-11-R在細胞生長曲線和細胞週期的分布(G1期: 63% vs. 61%;S期: 28% vs. 31%;G2/M期: 7% vs. 7%以及sub-G1期: 1.5% vs. 2.2%)沒有差異;在細胞型態上沒有顯著差異。利用流式細胞儀分析,發現MV-4-11-R表現較多的CD56(22.6% vs.37%)、CD16(5.7 % vs.8.8%)及較少的HLA-DR(12.7% vs.2.4%)。另外,也觀察到MV-4-11-R細胞中糖基化FLT3蛋白下降,其p-FLT3的磷酸化程度也較MV-4-11-P少。進一步分析FLT3-ITD的下游,結果顯示MV-4-11-R細胞中Stat5α之Tyr694、CREB之Ser133的磷酸化程度下降。關於Ara-C代謝酶的檢測,觀察到MV-4-11-P和MV-4-11-R在hENT1 mRNA (0.97 vs.0.74)(P=0.22)、DCK mRNA(0.33 vs.0.30)(P=0.48)以及NT5C2 mRNA(1.10 vs.1.45)(P=0.19)沒有顯著的差異。在多重抗藥性基因的檢測顯示,MV-4-11-P和MV-4-11-R在MDR1 mRNA(12.0x10-5 vs. 9.0 x10-5)(P=0.68)和MRP mRNA(0.18 vs.0.15)(P=0.31)表達沒有顯著的差異。接著,分別利用不同組的蛋白晶片分析這兩株細胞諸多蛋白的蛋白量或其磷酸化程度,例如MV-4-11-R中有p53之Ser15(像素密度: 672 vs. 4048)、Ser46(像素密度: 1242 vs.3725)以及Ser392(像素密度: 802 vs. 2981)的磷酸化程度增多。在磷酸酶蛋白晶片觀察到MV-4-11-R中ERK1/2之Thr202/Thr204,Thr185/Tyr187(像素密度: 956 vs. 6675)、Akt之Ser473(像素密度: 1132 vs. 1219)、MEK1/2之Ser18/Ser22,Ser22/Ser26(像素密度: 547 vs. 898)以及 p53之Ser15(像素密度: 605 vs.5896)、Ser46(像素密度: 1080 vs.4340)以及Ser392 (像素密度: 1529 vs. 4143)的磷酸化程度增多。MV-4-11-R中Stat5α之Tyr694(像素密度: 2441 vs.986)、Stat5β之Tyr699(像素密度: 4302 vs.1319)、Stat5α/β之Tyr694(像素密度: 3562 vs.1067)以及CREB之Ser133(像素密度: 5896 vs.606)的磷酸化程度減少。另外,在酪胺酸激酶蛋白晶片也發現MV-4-11-R中Axl之磷酸化蛋白量(像素密度: 5550 vs. 7110)比MV-4-11-P來的多,這些結果都以西方墨點進行確認。進一步檢測細胞中mRNA表現情況以及p53的基因序列,結果發現MV-4-11-P和MV-4-11-R在Axl mRNA(0.02 vs.0.04)(P=0.33)和Gas6 mRNA(0.45 vs. 0.57)(P=0.17)表達無顯著的差異。在基因序列,則發現這兩株細胞都具有p53基因突變,其中MV-4-11-P帶有R248W突變;MV4-11-R則帶有R248W和D281G突變。
總體來說,實驗室所建立出來MV-4-11-R細胞確實對Ara-C產生抗藥性。從我們的實驗結果顯示p53-D281G、Axl、Akt以及ERK1/2是造成MV-4-11-R對Ara-C產生抗藥性的可能原因。


Ara-C is a chemotherapeutic drug that commonly used in acute myeloid leukemia (AML).However, a substantial amount of patients suffer from relapse after remission. Drug resistance is the primary cause of leukemia chemotherapy failure. Although numerous mechanisms of drug resistance have been described, they are still not able to fully explain the development of resistance to Ara-C. To further investigate the mechanisms of resistance to Ara-C, we established Ara-C resistance leukemia cell lines from MV-4-11, which is known as MV-4-11-R. Cell viability showed that MV-4-11-R (IC50 =0.26 μM) were 13 fold resistance to Ara-C than parental cell line MV-4-11-P. There were no significant differences in the cell growth, cell cycle distribution (G1 phase: 63% vs. 61%;S phase: 28% vs. 31%;G2/M phase: 7% vs. 7% and sub-G1: 1.5% vs. 2.2%) and morphology between MV-4-11-P and MV4-11-R. The MV-4-11-R cells have more with CD56 (22.6% vs.37%) and CD16 (5.7 % vs.8.8%) expression, less with HLA-DR (12.7% vs.2.4%) expression. The expression of glycosylated FLT3 was found to be decreased in MV-4-11-R cells. Reduction of glycosylated FLT3 in MV-4-11-R was associated with decreased Stat5α and CREB activation. To investigate the mechanism underlying Ara-C resistant in MV-4-11-R, mRNA levels of Ara-C metabolizing enzymes and multidrug resistance gene were measured. There were no significant differences in hENT1 mRNA (0.97 vs.0.74)(P=0.22), DCK mRNA (0.33 vs.0.30)(P=0.48), NT5C2 mRNA (1.10 vs.1.45)(P=0.19), MDR1 mRNA (12.0x10-5 vs. 9.0 x10-5)(P=0.68) and MRP mRNA (0.18 vs.0.15)(P=0.31) between MV-4-11-P and MV-4-11-R.By using various kinds of Proteosome ProfilerTM Antibody Arrays, we found that increase of p-p53 protein Ser15 (pixel density: 672 vs. 4048), Ser46 (pixel density: 1242 vs. 3725) and Ser392 (pixel density: 802 vs. 2981) in MV-4-11-R cells. Human Phospho-kinase Antibody Array showed that p-ERK1/2 Thr202/Thr204,Thr185/Tyr187 (pixel density: 956 vs. 6675), p-Akt Ser473 (pixel density: 1132 vs. 1219), p-MEK1/2 Ser18/Ser22,Ser22/Ser26 (pixel density: 547 vs. 898) and p-p53 Ser15 (pixel density: 605 vs. 5896), Ser46 (pixel density: 1080 vs. 4340) and Ser392 (pixel density: 1529 vs. 4143) was increased in MV-4-11-R. While p-Stat5α Tyr694 (pixel density: 2441 vs. 986), p-Stat5β Tyr699 (pixel density: 4302 vs. 1319), p-Stat5α/β Tyr694 (pixel density: 3562 vs. 1067) and p-CREB Ser133 (pixel density: 5896 vs. 606) was decreased in MV-4-11-R. From the results of Human Phospho-RTK Antibody Array, we found that p-Axl (pixel density: 5550 vs. 7110) protein was increased in MV-4-11-R cells. We have confirmed these results by western blot.We also analyzed the the Axl and Gas6 mRNA expression and p53 gene status by DNA sequencing. The results showed that both Axl mRNA (0.02 vs. 0.04)(P=0.33) and Gas6 mRNA (0.45 vs. 0.57)(P=0.17) expression were no significant difference between MV-4-11-P and MV-4-11-R. The DNA sequencing results showed that MV-4-11-P cells harbored R248W mutation whereas MV-4-11-R cells harbored R248W and D281G mutations.
As results, we established Ara-C resistant cell line – MV-4-11-R. Our results demonstrated the acquisition of Ara-C resistance with aberrant expression of p53-D281G, Axl, Akt and ERK1/2.


目錄 I
圖目錄 V
表目錄 VII
縮寫表 VIII
摘要 IX
Abstract XI
第一章 前言 1
1.1 急性骨髓性白血病簡介 1
1.1.1 急性骨髓白血病(Acute Myeloid Leukemia,AML) 1
1.1.2 AML之分類 1
1.1.3 AML之治療 1
1.1.3.1 前導性治療(Induction Therapy) 1
1.1.3.2 鞏固性治療(Consolidation Therapy) 2
1.2 阿糖胞苷簡介 2
1.2.1 阿糖胞苷(Cytarabine,Ara-C) 2
1.2.2 阿糖胞苷的抗藥性 2
1.2.3 Ara-C抗藥性與基因突變的研究 3
1.3 TP53基因的簡介 4
1.3.1 p53突變與腫瘤的相關性 5
1.3.2 突變p53(mutp53)的“功能缺失”與“功能獲得” 6
1.3.3 p53與Ara-C的關係 6
1.4 FLT3-ITD(fms-like tyrosine kinase 3-internal tandem duplication) 6
1.5 多重抗藥基因1(Multidrug resistance 1,MDR1) 7
1.6 多藥耐藥相關蛋白(Multi-drug related protein,MRP) 8
1.7 骨髓細胞白血病蛋白-1(Myeloid cell leukemia 1,Mcl-1) 8
1.8 酪胺酸激酶(Protein Tyrosine Kinase,PTK) 8
1.8.1 Receptor Tyrosine Kinase AXL 10
第二章 研究目的 13
第三章 材料與方法 14
3.1 材料 14
3.1.1 細胞 14
3.1.2 儀器設備 14
3.1.3 藥品 15
3.1.4 抗體 17
3.1.5 試劑組 18
3.1.6 葯品與試劑配置 18
3.2 方法 20
3.2.1 細胞培養 20
3.2.2 細胞生長曲線的分析 20
3.2.3 細胞抑殺試驗(MTS assay) 20
3.2.4 Cytospin 20
3.2.5 劉式染色 21
3.2.6 白血球表面抗體螢光染色 21
3.2.7 周邊血單核球細胞(PBMC)分離 21
3.2.8 細胞萃取物製備 21
3.2.9 蛋白質定量 22
3.2.10 西方墨點法(Western Blotting) 22
3.2.11 DNA萃取 22
3.2.12 RNA萃取 23
3.2.13 反轉錄聚合酶連鎖反應(RT-PCR) 24
3.2.14 PCR聚合酶連鎖反應 24
3.2.15 2%洋菜膠的製備與電泳分析 24
3.2.16 聚合酶連鎖反應之純化 25
3.2.17 序列分析 25
3.2.18 即時監控聚合酶連鎖反應 25
3.2.19 對Cytarabine有抗藥性細胞之培養 26
3.2.20 Pyrosequencing 26
3.2.21 細胞週期分析(Cell cycle analysis) 27
3.2.22 Human Phospho-Kinase Array/Human Phospho-RTK Array 27
3.2.23 統計方法 28
第四章 實驗結果 29
4.1 Ara-C (Cytarabine)對MV-4-11細胞之毒殺性 29
4.2 細胞生長曲線與細胞週期在MV-4-11-P與MV4-11-R細胞中的差異 29
4.3 細胞型態與表面抗原在MV-4-11-P與MV4-11-R細胞中的差異 29
4.4 p-FlT3和Total FLT3在MV-4-11-P與MV4-11-R細胞中的差異 30
4.5 hENT1、DCK以及NT5C2的mRNA表現在MV-4-11-P與MV4-11-R細胞
中的差異 30
4.6 MDR1和MRP的mRNA表現在MV-4-11-P與MV4-11-R細胞中的差異 30
4.7 凋亡相關之蛋白在MV-4-11-P與MV4-11-R細胞中的差異 31
4.8 磷酸酶之磷酸化程度在MV-4-11-P與MV4-11-R細胞中的差異 31
4.9 p53基因在MV-4-11-P與MV4-11-R細胞中的差異 32
4.10 酪胺酸激酶之磷酸化程度在MV-4-11-P與MV4-11-R細胞中的差異 32
4.11 Axl和Gas6的mRNA表現在MV-4-11-P與MV4-11-R細胞中的差異 32
4.12 XL-184處理MV-4-11-R可抑制ERK之Thr202/Tyr204與Akt之Ser473的磷酸化,但無法抑制Axl的磷酸化 33
4.13 R428處理MV-4-11-R可抑制ERK之Thr202/Tyr204與Akt之Ser473的磷酸化,但無法抑制Axl的磷酸化 33
4.14 Mcl-1的mRNA表現和蛋白表現在MV-4-11-P與MV4-11-R細胞中的差異 34
4.15不同藥物對MV-4-11-P與MV4-11-R細胞之毒殺性 34
第五章 討論 36
第六章 未來展望 44
第七章 參考文獻 45
圖 56
表 83
附圖 86
附表 95


[1]Robak T, Wierzbowska A. Current and emerging therapies for acute myeloid leukemia. Clin Ther.2009 Sep;31(2):2349-70.
[2]Danial G.T. Disruption of differentiation in human cancer: AML shown the way. Nat Rev Cancer 2003 Feb;3(2):89-01
[3]Margaret R, O’Donnell, MD.Acute Leukemias. Cancer Management:14th
[4]Lanba JK. Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657-74
[5]Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011 Feb;29(5):487-94
[6]Galmarini CM, Cros E, Thomas X, Jordeheim L, Dumontet C. The prognostic value of cN-II and cN-III enzymes in adult acute myeloid leukemia. Haemotologica,2005 Dec;90(12):1699-01
[7]Hubeek I, Stam RW, Peters GJ, Broekhuizen R, Meijerinik JP, van Wering ER, Gibson BE, Creutzig U, Zwaan CM, Cloos J, Kuik DJ,Pieters R, Kaspers GJ. The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivy in childhood acute myeloid leukaemia. Br J Cancer.2005 Dec;93(12):1388-98
[8]Veuger MJ, Honders MW, Spoelder HE, Willemze R, Barge RM. Inactivation of deoxycytidine kinase and overexpression of P-glycopreotein in AraC and daunorubicin double resistant leukemic cell lines. Leuk Res.2003 May;27(5):445-53
[9]Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer.2004 Oct;4(10):793-05
[10]Prives C, Hall PA. The p53 pathway. J Pathol.1999 Jan;187(1):112-26
[11]Zhan Q, Antinore MJ, Wang XW. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene.1990 May;18(18):2892-00
[12]Liversey KM, Kang R, Vernon P, Buchser W, Loughran P, Watkins SC,Zhang L, Manfredi JJ, Zeh HJ 3rd, Li L, Lotze MT, Tang D. p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res.2012 Apr;72(8):1996-05
[13]Shen L, Sun X, Fu Z, Yang G, Li J, Yao L. The fundamental role of the p53 pathway in tumor metabolism and its implication in tumor therapy. Clin Cancer Res.2012 Mar;18(6):1561-07
[14]CR Boland, MF Lucianni C Gasche, A Goel. Infection, inflammation and gastrointenstinal cancer. Gut.2005 Sep;54(9):1321-31
[15]Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev.2012 Jun;26(12):1268-86
[16]Gaidano G, Ballerini P, Gong JZ. P53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci USA.1991 Jun;88(12):5413-07
[17]H Ahuja, M Bar-Eli,Z Arlin, S Advani, S L Allen, J Goldman, D Snyder, A Foti, M Cline. The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia. J Clin Invest.1991 Jun;87(6):2042-07
[18]Fenaux P, Preudhomme C, Lai JL, Quiquandaon I, Jonveaux P, Vanrumbeke M, Sartiaux C, Morel P, Loucheux-Lefebvre MH, Bauters F. Mutations of the p53 gene in B-cell chronic lymphocytic leukemia: a report on 39 cases with cytogenetic analysis. Leukemia.1992 Apr;6(4):246-50
[19]Fenaux P, Jonveaux P, Quiquandon L, Lai JL, Pignon JM, Loucheux-Lefebyre MH, Bauters F, Berger R, Kerckaert JP. p53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood.1991 Oct;78(7):1652-07
[20]Di Agaostino S, Strano S, Emillozzi V, Zerbine V, Mottolese M, Sacchi A, Blandino G, Piaggio G. Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer cell.2006 Sep:10(3):191-02
[21]Wattel E, Preudhomme c, Hecquet B, Vanrumbeke M, Quesnel B, Derivite I, Morel P, Fenaux P. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood.1994 Nov;84(9):3148-57
[22]Yin B, Kogan SC, Dickins RA, Lowe Sw, Largaespada DA. Trp53 loss during in vitro selection contributes to acquired Ara-C resistance in acute myeloid leukemia. Exp Hematol.2006 May;34(5):631-41
[23]Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood.2002 Sep;100(5):1532-42
[24]Williams AB, Li L, Nguyen B, Brown P, Levis M, Small D. Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood.2012 Oct;120(15):3069-79
[25]Hayakawa F, Towatari M, Kiyoi H, Tanimoto M,Kitamura T, Saito H, Naoe T. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3 dependent cell lines. Oncogene.2000 Feb;19(5):624-31
[26]Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishirumura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R,Ohno R, Naoe T. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood.2001 Apr;97(8):2434-39
[27]Grafone T, Palmisano M, Nicci C, Storti S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncology Reviews.2012 Apr;6(8):65-74
[28]Jin G, Matsushita H, Asai S, Tsukamoto H,Ono R, Nosaka T, Yahata T, Takahashi S, Miyachi H. FLT3-ITD induces ara-c resistance in myeloid leukemia cells through the repression of the ENT1 expression. Biochem Biophys Res Commum.2009 Dec;390(3):1001-06
[29]Wang L, Yang CP, Horwitz SB, Trail PA, Casazza AM. Reversal of the human and murine multidrug-resistance phenotype with megestrol acetate. J Cancer Chemotherapy Pharmocol.1994 Jan;34(2):96-02
[30]Mannsson E, Paul A, Lofgen C, Ullberg K, Paul C, Eriksson S, Albertioni F. Cross-resistance to cytosine arabinoside in a multidrug-resistance human promyelocytic cell line selected for resistance to doxorubicin:implications for combination chemotherapy. Br J Haematol.2001 Sep;114(3):557-65
[31]Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the human mdr1 gene by Ras and p53. J Science.1992 Jan;255(5043):459-62
[32]Legrand O, Zittoun R, Marie JP. Role of MRP1 in multidrug resistance in acute myeloid leukemia. Leukemia.1999 Apr;13(4):578-84
[33]Sonneveld P, Peiters R. The prognostic significance of membrane transport associated multidrug resistance (MDR) proteins in leukemia. Int J Clin Pharmacol Ther.2000 Mar;38(3):94-10
[34]Borg AG, Burgess R, Green LM, Scheper RJ, Liu Yin JA. P-glycoprotein and multidrug resistance associated protein, but not lung resistance protein, lower the intracellular daunorubicin accumulation in acute myleloid leukemic cells. Br J Haematol.2000 Jan;108(1):48-54
[35]Zhou P, Qian L, Craig RW. Mcl-1. a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. Blood.1997 Jan;89(2):630-43
[36]Kasper S, Breitenbuecher F, HeideI F, Hoffarth S, Markova B, Schuler M, Fischer T. Targeting Mcl-1 sensitizes FLT3-ITD positive leukemias to cytotoxic therapies. Blood Cancer J.2012 Mar;2(3):e60.
[37]McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta,2007 Aug;1773(8):1263-84
[38]VL Grandage, RE Gale, DC Linch, A Khwaja. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kB, MAPkinase and p53 pathways. Leukemia.2005 Feb;10(1038):,586-94
[39]Blume-Jensen P, Hunter T. Oncogenic kinase signaling. Nature.2001 May;411(6835):355-65
[40]Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene.2000 Nov;19(49):5548-57
[41]Robertson SC, Tynan JA, Donoqhue DJ. RTK mutations and human syndromes when good receptors turn bad. Trends Genet.2000 Jun;16(6):265-71
[42]Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, Lai GM, Chuang SE. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett.2008 Sep;226(2):314-24
[43]O’Bryan JP, Frye RA, Coqswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET. Axl, a transforming gene isolated from primary human myeloid leukemia cells, encoded a novel receptor tyrosine kinase. Mol Cell Biol.1991 Oct;11(10):5016-31
[44]Chung BI, Malkowicz SB, Nguyen TB, Libertino JA, McGarvey TW. Expression of the proto-oncogene Axl in renal cell carcinoma. DNA Cell Biol.2003 Aug;22(8):533-40
[45]Sawabu T, Seno H, Kawashima T, Fukuda A, Uenoyama Y, Kawada M, Kanda N, Sekikawa A, Fukui H, Yanagita M, Yoshibayashi H, Satoh S, Sakai Y, Nakano T, Chiba T. Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway. Mol Carcinog.2007 Feb;46(2):155-64
[46]Shieh YS, Lai CY, KaoYR,Shiah SG, Chu YW, Lee HS, Wu CW. Expression of Axl in Lung Adenocarcinoma and Correlation with Tumor Progression. Neoplasia.2005 Dec;7(12):1058-64
[47]Sun W, Fujimoto J, Tamaya T. Coexpression of Gas6/Axl in human ovarian cancers. Oncology.2004 Sep;66(6):450-57
[48]Benzakour O, Gely A, Lara R, Coronas V. Gas-6 and protein S : vitamin K-dependent factors and ligands for the TAM tyrosine kinase receptors family. Med Sci(Paris).2007 Oct;23(10):826-33
[49]Nagata K, Ohashi K, Nakano T, Arita H, Zong C, Hanafusa H, Mizuno K. Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky and Mer receptor tyrosine kinases. J Biol Chem.1996 Nov;271(47):300322-27
[50]Linger RM, Keating AK, Earp HS, Graham DK. TAM Receptor Tyrosine Kinase: Biologic Functions, Signaling and Potential TherapeaticTargeting in Human Cancer. Adv Cancer Res.2008 Jul;10(100):35-83
[51]Mudduluru G, Allgayer H. The human receptor tyrosine kinase Axl gene-promoter characterization and regulation of constitutive expression by Sp1,Sp3 and CpG methylation. Biosci Rep.2008 Jun;28(3):161-76
[52]Hermeking H. MicroRNAs in the p53 network: micromanagement of tumor suppression. Nat Rev Cancer.2012 Sep;12(9):612-26
[53]Vaughan CA, Singh S, Windle B, Yeudall WA, Frum R, Grossman SR, Deb SP, Deb S. Gain-of-Function activity of mutant p53 in Lung Cancer through up-regulation of Receptor Protein Tyrosine Kinase Axl. Genes Cancer.2012 Jul;3(708):491-02
[54]Hasanbasic I, Cuerguis J, Varnum B, Blostein MD.Intracellular signaling pathways involved in Gas6-Axl mediated survival of endothelial cells. AM J Physiol Heart Circ Physiol. 2004 Sep;287(3):1207-13
[55]Tai KY, Shieh YS, Lee CS, Shiah SG, Wu CW. Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1. Oncogene.2008 Jul;27(29):4044-55
[56]Reed JC. Bcl-2 family proteins : regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol.1997 Oct,34(4):9-19
[57]Anker L, Ohgaki H, Ludeke BI, Herrmann HD, Kleihues P, Westphal M. p53 protein accumulation and gene mutations in human glioma cell lines. Int J Cancer.1993 Dec;55(6):982-87
[58]Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH. Cabozantinib(XL184),a novel MET and VEGFR2 inhibitor, stimultaneously suppresses metastasis, angiogenesis and tumor growth. Mol Cancer Ther.2011 Dec;10(19):2293-08
[59]Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Torneros A, Yu J, Heckrodt TJ, Zhang J, Ding P, Apatira A, Chua J, Brandt R, Pine P, Goff D, Singh R, Payan DG, Hitoshi Y. R428, a selective small molecule inhibitor of Axl kinase,blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res.2010 Feb;70(4):1544-54
[60]Yoshimoto G,Miyamoto T,Jabbarzadeh-Tabrizi S, lino T, Rocnik JL,Kikushige Y, Mori Y, Shima T, Iwasaki H, Takenaka Km Nagafuji K, Mizuno S, Niiro H, Gilliland GD, Akashi K. FLT3-ITD up-regulates Mcl-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood.2009 Dec;114(24):5034-43
[61]Lippert TH, Ruoff HJ, Volm M. Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure. Arzneimittelforschung.2008 Jun;58(6):261-64
[62]Di Bona E, Sartori R, Zambello R, Gurecini N, Madeo D, Rodeghiero F. Prognostic significance of CD56 antigen expression in acute myeloid leukemia.Haematologica.2002 Mar;87(3):250-56
[63]Raspadorii D, Damiani D, Lenoci M, Rondelli D, Testoni N, Nardi G, Sestigiani C, Mariotti C, Birtolo S, Tozzi M, Lauria F. CD56 antigenic expression in acute myeloid leukemia: impact on clinical outcome. Leukemia.2001 Aug;15(8):1161-64
[64]Raspadorii D, Damiani D, Lenoci M, Rondelli D, Testoni N, Nardi G, Sestigiani C, Mariotti C, Birtolo S, Tozzi M, Lauria F. CD56 and PGP expression in acute myeloid leukemia: impact on clinical outcome. Hematologica.2002 Nov;87(11):1135-40
[65]Suvannasankha A, Minderman H, Sait SN, Stewart CC, Greco WR, Baer MR. Expression of the neural cell adhesion molecule CD56 is not associated with P-glycoprotein overexpression in core-binding factor acute myeloid leukemia. Leuk Res.2004 May;28(5):449-55
[66]Mathiot C, Teillaud JL, Elmalek M, Mosseri V, Euller-Ziegler L, Daragon A, Grosbois B, Michaux JL, Facon T, Bernard JF. Correlation between soluble serum CD16(sCD16) levels and disease stage in patients with multiple myeloma. J Clin Immunol.1993 Jan;13(1):41-48
[67]Sconocchia G, Zlobec I, Lugli A, Calabrese D, Iezzi G, Karamitopoulou E, Patsouris ES, Peros G, Horcic M, Tornillo L, Zuber M, Droeser R, Muraro MG, Mengus C, Oertli D, Ferrone S, Terracciano L, Spagnoli GC. Tumor infiltration bu FcγRII (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma. Int J Cancer.2011 Jun;128(11):2663-72
[68]Termijtelen A, van Lewuwen A, van Rood JJ . HLA-linked lymphocyte activating determinants. Immunol Rev.1982 Sep;66(1):79-01
[69]Brian A Webber, Melissa M Cushing, Shiyong Li. Prognostic Significance of Flow Cytometric Immunophenotyping in Acute Myeloid Leukemia. Int J Clin Exp Pathol.2008 Jan;1(2):124-33
[70]Pinto A, Maio M, Attadia V, Zappacosta S, Cimino R. Modulation of HLA-DR antigens expression in human myeloid leukaemia cells by cytarabine and 5-aza-2’deoxycytidine. Lancet.1984 Oct;2(8407):867-68
[71]Han LN, Zhou J, Schuringga JJ, Vellenga E. Treatment strategies in acute myeloid leukemia. Chin Med J (Engl).2011 May;124(9):1409-21
[72]Materlli AM, Evangelisti C, Chiarini F, McCubrey JA. The phosphatidylinositol 3-kinase/Akt/mTOR signaling netweork as a therapeutic target in acute myelogenous leukemia patiens. Oncotarget.2010 Jun;1(2):89-03
[73]Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood.2002 Sep;100(5):1532-42
[74]Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD, Gerke V, Schmidt-Arras DE, Berdel WE, Muller-Tidow C, Mann M, Serve H. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell.2009 Oct;36(2):326-39
[75]Yoshimoto G, Miyaomoto T, Jabbarzadeh TS, lino T, Rocknik JL, Kikushige Y, Mori Y, Shima T, Iwasaki H, Takenaka K, Nagafuji K, Mizuno S, Niiro H, Gilliland GD, Akashi K. FLT3-ITD up-regulates Mcl-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood.2009 Dec;114(24):5034-43
[76]Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF. The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol. 1999 Sep;19(9):6195-06
[77]Liu H, Ma Y, Cole SM, Zander C, Chen KH, Karras J, Pope RM. Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. Blood.2003 Jul;102(1):344-52
[78]Liu XH, Yu EZ, Li YY, Kagan E. HIF-1 aplha has an-anti-apoptotic effect in human airway epithelium that is mediated via Mcl-1 gene expression. J Cell Biochem.2006 Mar;97(4):755-65
[79]Inuzuka H, Fukushima H, Shaik S,Liu P, Lau AW, Wei W. Mcl-1 ubiquitination and destruction. Oncotarger.2011 Mar;2(3):239-44
[80]Leisewitz AV, Zimmeraman EI, Huang M, Jones SZ, Yang J, Graves LM. Regulation of ENT1 expression and ENT1-dependent nucleoside transport by c-Jun-N-terminal kinase. Biochem Biophys Res Commun.2011 Jan;404(1):370-75
[81]Jin G, Matsuhita H, Asai S, Tsukamoto H, Ono R, Nosaka T, Yahata T, Takahashi S, Miyachi H. FLT3-ITD induced ara-c resistance in myeloid leukemic cells through the repression of the ENT1 expression. Biochem Biophys Res Commun. 2009 Dec;390(3);1001-06
[82]Brooks CL, Gu W. Ubiquitionation, phosphorylation and acetylation : the molecular basis for p53 regulation. Curr Opin Cell Biol. 2003 Apr;15(2):164-71
[83]Toledo F, Wahi GM. Regulating the p53 pathawy: in vitro hypothese, in vivo veritas. Nat Rev Cancer.2006 Dec;6(12):909-23
[84]Gu B, Zhu WG. Surf the post-translational modification network of p53 regulation. Int J Biol Sci.2012 May;8(5):672-84
[85]Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012 Jun;26(12):1268-86
[86]Hasanbasic I, Cuerquis J, Varnum B, Blostein MD. Intracellular signaling pathways involved in Gas6-Axl mediated survival of endothelial cells. Am J physiol Heart Circ Physiol.2004 Sep;287(3):H1207-13
[87]Sato T, Yang T, Knapper S, White P, Smith BD, Galkin S, Small D, Burnett A, Lewis M. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood.2011 Mar;117(12):3286-93
[88]Song JH, Kim SH, Kim HJ, Hwang SY, Kim TS. Alleviation of the drug resistant phenotype in idarubicing and cytosine arabinoside double-resistant acute myeloid leukemia cells by indomethacin. Int J Oncol.2008 Apr;32(4):931-36
[89]Dartsch DC, Gieseler F. Repair of idarubicin-induced DNA damage: a cause of resistance? DNA Repair(Amst).2007 Nov;6(11):1618-28



QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top