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항암제 내성 백혈병 및 폐암 세포주에서 방사선에 대한 교차내성 기전의 규명

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Author(s)
徐海東
Issued Date
2004
Abstract
This study was attempted to explore the cross resistance of chemoresistant cancer cells to radiation and its resistance mechanisms. Cytotoxicity and mRNA expression were determined by MTT assay and cDNA microarray and/or RT-PCR method, respectively. Two doxorubicin -resistant cells, AML-2/DX100 and SK-MES-1/DX1000, and a paclitaxel-resistant cell, SK-MES-1/PT4000, showed the multidrug resistance phenotypes by overexpressing multidrug resistant associated protein (MRP) in AML-2/DX100 and P-glycoprotein in other cells. Three resistant cells showed cross resistance to radiation. The radioresistance of AML-2/DX100 were not influenced by an MRP inhibitor (probenecid), Pgp inhibitor (PSC833), an inhibitor of metallothionein sythesis (propargylglycine), an inhibitor of glutathione S-transferase (buthionine sulfoxamine) and adhesion with fibronectin. AML-2/DX100 cells showed increased defense mechanisms against endogenous reactive oxygen species (ROS) even though they are supersensitive to exogenous hydrogen peroxide when compared to AML-2/WT, suggesting that an anti-oxidant adaptation against ROS occurred. cDNA microarrays for 8000 human genes revealed that among 21 anti-oxidant genes, each four gene was up- and down-regulated more than 1.5-fold in AML-2/DX100 as compared to AML-2/WT. The mRNA expression of glutathione S -transferase Pi, peroxiredoxin 2, thioredoxin 2, and glutaredoxin was elevated whereas that of peroxiredoxin 3, metallothionein-1F, superoxide dismutase 2, and thioredoxin reductase 1 was depressed. Radiation increased bax but not bcl-2 translocation into the mitochondria of AML-2/WT cells, thereby induced cytochrome c release from the mitochondria and consequently caspase 3 activation whereas it increased more bcl-2 but not bax translocation into the mitochondria of AML-2/DX100 cells than those of AML-2/WT cells. Interestingly, AML-2 /DX100 cells showed higher expression of melanoma antigens (MAGEA2, MAGEA4, MAGEB2 and MAGEA6) than that of AML-2/DX100 cells. The SK-MES-1/Rad cells that have been repeatedly irradiated for 6 months did not show radioresistance but chemosensitivity.
Overall, it appears that the radioresistance mechanisms of AML-2 /DX100 cells may have nothing to do with MRP, P-glycoprotein, metallothionein and glutathione S-transferase but something to do with altered mitochondrial translocation of Bax and up-regulation of MAGE expression. It is thought that radiotherapy if possible should be done before chemotherapy.
Alternative Title
Mechanisms of cross resistance of chemoresistant leukemic and lung cancer cell lines to radiation
Alternative Author(s)
Xu, Haidong
Affiliation
朝鮮大學校 大學院
Department
일반대학원 의학과
Advisor
崔哲熙
Awarded Date
2005-02
Table Of Contents
TABLE OF CONTENTS
TABLE OF CONTENTS = Ⅰ
LIST OF TABLE = Ⅲ
LIST OF FIGURES = Ⅳ
ABSTRACT = Ⅴ
Ⅰ. 서론 = 1
Ⅱ. 연구재료 및 방법 = 6
1. 세포 배양과 내성 세포주의 선별 = 6
2. 세포 독성 실험 = 7
3. 형광탐식자를 이용한 반응성 산소종의 측정 = 9
4. RT-PCR 분석 = 9
5. DNA chip = 11
6. Western blot 분석 = 13
7. 방사선이 bax translocation과 cytochrome c유리에 미치는 영향 = 14
Ⅲ. 결과 = 15
1. 항암제 내성세포의 선별 및 내성기전의 규명 = 15
2. 항암제 내성세포에서의 방사선의 세포독성 효과 = 16
3. 폐암 세포의 반복 방사선 조사효과 = 16
4. 방사선 반복 조사한 폐암세포에서의 항암제의 세포독성 효과 = 16
5. AML-2/DX100세포에서 반응성산소종에 대한 방어기전의 변화 = 17
6. AML-2/DX100세포에서의 내성기전과 방사선내성과의 관계 = 17
7. AML-2/DX100세포에서 방사선이 bcl-2 및 bax의 발현과 미토콘드리아로 translocation과 cytochrome c 유리에 미치는 영향 = 18
8. AML-2/DX100세포에서 MAGE의 발현 = 18
Ⅳ. 고찰 = 34
Ⅴ. 결론 = 39
Ⅵ. 감사의 글 = 41
Ⅶ. 참고문헌 = 42
Degree
Master
Publisher
朝鮮大學校 大學院
Citation
徐海東. (2004). 항암제 내성 백혈병 및 폐암 세포주에서 방사선에 대한 교차내성 기전의 규명.
Type
Dissertation
URI
https://oak.chosun.ac.kr/handle/2020.oak/5789
Appears in Collections:
General Graduate School > 3. Theses(Master)
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