臺灣博碩士論文加值系統

癌細胞對一種化學治療藥物產生抗藥性時，也會對其他作用或結構不同的藥物產生抗藥性，稱為多重抗藥性。癌細胞可因許多因素產生多重抗藥性，本論文的主題是研究多重抗藥性之形成及其逆轉之機制。
論文第一部分主要證明MRP1表現和化學治療藥物多重抗藥性的關係。我們用RT-PCR檢驗十幾個癌細胞株，結果發現MRP1 mRNA在所有的細胞中都存在。再將MRP1 mRNA做定量RT-PCR，則發現具抗藥性的人類乳癌細胞MCF7/VP、MCF7/ADR及血癌細胞HL60/AR三個抗藥細胞株有過量的MRP1表現。檢驗亦發現這類抗藥細胞已具有多組複製的MRP1基因。這部分研究支持MRP1在多重抗藥性中扮演重要的角色。
第二部份論文是討論氧化砷的抗藥性。氧化砷是新的抗血癌的藥物，在這研究中，我們探討氧化砷抗藥性和GSH系統那一成員較有關聯。在十七株癌細胞細胞毒性的試驗發現，氧化砷對膀胱癌、消化道癌的毒性較高，肝癌及非小細胞肺癌細胞則有很高的內在抗藥性。經檢驗發現，十七個細胞株中，GST-pi的表現和細胞毒性無關。而MRP1只在兩株抗藥性高的細胞中表現(H460及BFTC909)，在其它抗藥性高的細胞中(如Hep3B, MCF7)則無表現。GSH則在所有的高內在抗藥性的細胞株中都很高，在所有的低抗藥性的細胞株中都很低，和氧化砷的抗藥性關聯最高。多重抗藥細胞MCF7/VP、MCF7/ADR及NTUB1/P14對砷有2-6倍的抗藥性。經檢驗發現MCF7/VP及MCF7/ADR的MRP1表現高，GSH含量則和MCF7/WT相等；NTUB1/P14和NTUB1比較，則GSH非常高，MRP1無表現。使用BSO抑制細胞GSH的合成，可將MCF7/VP及NTUB1/P14的氧化砷抗藥性完全逆轉。氧化砷抗藥性的研究結論為，此藥可能可以使用在膀胱癌或腸胃道癌的治療，氧化砷的抗藥性和GSH最有關，某些細胞則因MRP1過度表現而對氧化砷產生抗藥性。在設計氧化砷的臨床試驗時應考慮測量癌細胞GSH的含量，並考慮使用BSO增強氧化砷的效用。BSO的逆轉實驗也間接證明氧化砷是和GSH結合後由MRP1排出癌細胞的假說。
我們研究MRP1在多重抗藥性細胞的表現時，發現一些癌細胞不表現Pgp及MRP1，但仍具多重抗藥性。MCF7/MX是以mitoxantrone培養出的抗藥株，MCF7/TPT是以topotecan培養出的抗藥株，就具備這種特色。MCF7/MX 及MCF7/TPT細胞具有相似的表現型，稱為MX/TPT抗藥性，這是論文第三部份的主題。MCF7/MX及MCF7/TPT對mitoxantrone、topotecan及CPT-11有很高的抗藥性，對doxorubicin、VP16、camptothecin等藥則只有輕度抗藥性。以前多數學者相信拓蹼異構酵素第一型及第二型抑制劑間無交互抗藥性，而拓蹼異構酵素第一型抑制劑的抗藥性多是由癌細胞中拓蹼異構酵素第一型缺乏或突變引起的。在MCF7/MX中，第一型拓蹼異構酵素的量和MCF7/WT中相等。以DNA relaxation方法也證實在MCF7/MX及MCF7/WT中第一型拓蹼異構酵素的活性是相同的。以flowcytometry測量發現MCF7/MX及MCF7/TPT細胞中的topotecan量比MCF7/WT低很多、排除topotecan的速度也快很多。再加上已知MCF7/MX乃依靠ATP將mitoxantrone排出細胞，而MCF7/MX及MCF7/TPT 細胞並無p-glycoprotein或MRP過量表現，我們可以假設在MCF7/MX及MCF7/TPT細胞內存在一種未知的ATP-binding cassette 家族的蛋白質，這蛋白質對mitoxantrone, topotecan等藥物產生極高的抗藥性。在topotecan排除的研究中發現，MCF7/TPT細胞能將topotecan迅速排到細胞外，而MCF7/WT細胞則能將topotecan存在細胞中較長的時間。這種將藥物排到細胞外的機轉須依靠ATP之能量才能運作。研究中亦發現，使用一種抗生素novobiocin能部分逆轉topotecan及mitoxantrone 的抗藥性。在實驗中加入novobiocin能使MCF7/TPT細胞的topotecan 量及排除速率恢復如MCF7/WT細胞一樣。因此證明novobiocin乃抑制topotecan的排除，以達到逆轉topotecan抗藥性的結果。BCRP是一個新的ABC蛋白質，被認為和mitoxantrone抗藥性有關，MCF7/MX中的確BCRP的含量很高，但MCF7/TPT細胞中的BCRP含量雖比MCF7/WT多但和MCF7/MX相比仍很少，其意義有待進一步研究。
本研究第四個主題乃使用一個化學治療的逆轉劑tamoxifen進行臨床試驗。高劑量的tamoxifen可以逆轉和P-glycoprotein有關或無關的抗藥性。使用tamoxifen能使非小細胞肺癌細胞對cisplatin、VP-16的敏感度增加。我們進行一個第二期的臨床試驗，使用高劑量tamoxifen加上cisplatin、VP-16治療無法手術治癒的非小細胞肺癌的病人，結果發現腫瘤反應率為37.5%，一年存活率為44%，中間存活期為47星期，中間疾病無惡化存活期為21星期。這些結果都比以往只使用cisplatin及VP-16之治療結果為佳。使用毒性低的藥物當逆劑，提供了一種增進化學治療效用之途徑。
總結而言，在本研究中，我們支持了MRP1在多重抗藥性的角色。提出氧化砷可進行固態癌臨床試驗的基礎研究，證實GSH是影響氧化砷毒性的最主要因素，不論MRP1是否存在，都可用BSO成功逆轉氧化砷的抗藥性。我們亦描述一種新的多重抗藥表現型，可將喜樹鹼衍生物依抗藥性分為兩類，這是一種促進topotecan由細胞排除的機轉。抑制ATP的合成可以抑制這抗藥機轉。我們也找到此抗藥性的逆轉劑novobiocin，並證實逆轉抗藥性的機轉是抑制topotecan 由細胞排除。最後論文中提出使用高劑量tamoxifen當化學治療逆轉劑之可行性及效果在本研究中得到相當的支持。

Cancer cells exposed to certain chemotherapeutic agents can acquire cross-resistance to other structurally or functionally related or unrelated drugs, a phenomenon known as multidrug resistance. Multiple factors are known to confer resistance to chemotherapeutic agents. This thesis explores the emergence of multidrug resistance in cancer cells and the possibility of reversal of this resistance by relatively non-toxic drugs.
In the first part of my thesis studies, the role of multidrug-resistance associated protein 1 (MRP1) in multidrug resistant cancer cells was investigated. We tested MRP1 expression in several pairs of drug-sensitive and -resistant cancer cells by quantitative RT-PCR. MRP1 mRNA was expressed in all cells tested. Overexpression of MRP1 was found in MCF7/VP, MCF7/ADR and HL60/AR multidrug resistant cancer cells. Southern blot analysis demonstrated that MRP1 gene was amplified in MCF7/VP cells. My study supports that MRP1 overexpression confers resistance to multidrug resistance in cancer cells.
In the second part of the present study, we explored the mechanism of resistance in a novel chemotherapeutic agent, arsenic trioxide. The possibility of using arsenic trioxide in the treatment of solid tumor was tested. Cytotoxicity assay of arsenic trioxide in 17 cancer cell lines demonstrated that bladder cancer and gastrointestinal cancer cells were most sensitive to arsenic trioxide in addition to acute promyelocytic leukemic cells. Arsenic trioxide may induce apoptosis in NTU-B1 bladder cancer cells. On the other hand, non-small cell lung cancer cells and hepatocellular carcinoma cells were intrinsically most resistant to arsenic. The mechanism of arsenic resistance was investigated. through the correlation between glutathione, glutathione-s-transferase and MRP1 expression and arsenic toxicity. MRP1 was overexpressed in two cell lines (H460 and BFTC909) that were resistant to arsenic. But it is not overexpressed in all other resistant cell lines. There was no correlation of GST-pi expression and arsenic toxicity. One the other hand, GSH content of the cancer cells correlated well to intrinsic arsenic toxicity. Multidrug resistant MCF7/VP, MCF7/ADR and NTU-B1/P14 cells were cross-resistant to arsenic. MRP1 was overexpressed in MCF7/VP and MCF7/ADR cells but not in NTU-B1/P14 cells, while glutathione content was overexpressed in NTU-B1/P14 cells. Therefore, both MRP1 and glutathione overexpression may confer acquired resistance to cancer cells. Ten micromolar of BSO may completely reverse arsenic resistance in both NTU-B1/P14 and MCF7/VP cells. In conclusion, glutathione content may be the main determinant of arsenic toxicity. GSH-MRP1 system is the major route of arsenic detoxification. It is warranted to conduct arsenic trioxide clinical trials in solid tumors. Measurement of GSH content in cancer and normal tissues should be considered in the clinical trials.
In the third part of the study, we investigated a novel multidrug resistance phenotype, MX/TPT resistance. MCF7/MX cells are mitoxantrone-resistant and MCF7/TPT cells are topotecan-resistant human breast carcinoma cells. They contain several common resistance phenotypes. Both cells were resistant to mitoxantrone, topotecan and CPT-11 and were only slightly cross-resistant to camptothecin, doxorubicin and VP16. There was no P-glycoprotein or MRP1 overexpression in MCF7/MX or MCF7/TPT cells. Prior studies on topoisomerase I toxin resistance suggested that down-regulation and/or mutation of topoisomerase I was the main mechanisms of resistance. Our study, however, showed that DNA topoisomerase I activity and amount were not changed in MCF7/MX cells compared to MCF7/WT cells. Flowcytometric analysis demonstrated that topotecan accumulation was decreased in MCF7/MX as well as in MCF7/TPT cells. On the other hand, camptothecin accumulation was only slightly increased in MCF7/MX cells compared to MCF7/WT cells. Topotecan efflux was markedly enhanced in MCF7/TPT cells. Topotecan efflux was inhibited by pre-incubation in sodium azide in glucose free media to deplete cellular ATP. These results suggest that a novel ATP-binding cassette protein may confer MX/TPT resistance in these cells. We also found that novobiocin may partially reverse topotecan and mitoxantrone resistance in MCF7/TPT cells. The mechanism of novobiocin may be through inhibition of topotecan efflux of MCF7/TPT cells. Breast cancer resistance protein (BCRP) is a novel half ABC protein that was linked to mitoxantrone resistance. We found that BCRP was over-expressed in MCF7/MX cells but only vaguely expressed in MCF7/TPT300 cells. Further investigations are needed to decipher the role of BCRP in MX/TPT resistance.
High dose tamoxifen has been shown in the laboratory to reverse p-glycoprotein dependent and independent multidrug resistance. In the fourth part of the studies, we designed a phase II study to test the feasibility of using high dose tamoxifen plus cisplatin and VP16 in the treatment of inoperable non-small cell lung cancer patients. Forty patients were accrued to the study. The response rate was 37.5%. One-year survival was 44% and median survival was 47 weeks. Progression-free survival was 21 weeks. Our study suggests that reversing agents with chemotherapy may provide a new avenue to improve the effect of chemotherapy in the future.
In conclusion, we have demonstrated that MRP1 is involved in multidrug resistance in cancer cells. Arsenic trioxide is cytotoxic to bladder and gastrointestinal cancer cell lines. The main determinant of arsenic sensitivity is cellular glutathione content. GSH-MRP system is the main arsenic detoxification system in cancer cells. BSO may reverse arsenic resistance and can be tested in clinical trials. We also discover a novel topotecan/mitoxantrone resistance in MCF7/MX and MCF7/TPT cells. It is a non-p-glycoprotein, non-MRP1, energy-dependent topotecan efflux mechanism. The possibility of breast cancer resistance protein (BCRP) overexpression in these cells is explored. We also demonstrate that novobiocin may reverse MX/TPT resistance in these cells. The feasibility of using tamoxifen as a reversing agent for chemotherapy in clinical trials was also demonstrated in the study.

封面
誌謝
論文總目錄
圖目錄
縮寫表
中文摘要
ABSTRACT
PART I- INTRODUCTION
I.I. DRUG RESISTANCE IN CANCER CHEMOTHERAPY
1.2. CROSS-RESISTANCE AND MULTIDRUG RESISTANCE IN CANCER CHEMOTHERAPY
1.3. ATP BINDING CASSETTE (ABC) FAMILY PROTEIN
1.4. GLUTATHIONE SYSTEM AND MRPI
1.5. TOPOISOMERASE I TOXIN RESISTANCE
1.6. REVERSAL OF MDR
1.7. OVERVIEW OF THE STUDIES
1.8. OBJECTIVES OF THIS STUDIES
PART 2- MRPI EXPRESSION IN MDR CANCER CELLS
2.1. INTRODUCTION
2.2. MATERIAL AND METHODS
2.3. RESULTS
2.3.1. Mdr-I andMRPI RT-PCR in drug-sensitive and resistant cancer cells
2.3.2. Quantitative RT-PCR ofMRPI in drug-sensitive anc resistant cancer cells
2.3.3. MRPI DNA amplification in MCF7/VP cells
2.3.4. Quantitative RT-PCR of DNA topoisomerase I, lla and lip m drug-sensitive and -resistant cancer cells
2.4. DISCUSSION
PART 3
3.1. INTRODUCTION
3.1.1. Arsenic as an anticancer agent
3.1.2. Intrinsic resistance to arsenic
3.1.3. Arsenic resistance in multidrug resistant cancer cells
3.1.4. Reversal of arsenic resistance
3.2 MATERIALS AND METHODS
3.3. RESULTS
3.3.1. Cytotoxicity ofAs@C@ in cancer cells
3.3.2. DNA fragmentation
3.3.3. MRPI protein expression
3.3.4. GST-pi protein expression
3.3.5. GSH content in cancer cells.
3.3.6. Cytotoxicity of arsenic trioxide in drug-sensitive and resistant cells
3.3.7. MRPI expression in drug-sensitive and -resistant MCF7 andNTU-BI cells
3.3.8. GSH content in drug-sensitive and -resistant MCF7 andNTU-BI cells
3.3.9. ICioS ofBSO in drug-sensitive and -resistant MCF7 andNTU-BI cells
3.3.10. BSO reverses arsenic resistance in MCF7/VP and NTU-BI/P14 cells
3.4. DISCUSSION
PART 4 - MX/TPT RESISTANCE IN CANCER CELLS
4.1 BACKGROUND
4.1.1. Discovery ofMX/TPT resistance in MCF7/MX cells
4.1.2. Camptothecin resistance and topotecan resistance
4.1.3. Reversal ofMX/TPT resistance
4.2. MATERIAL AND METHODS
4.3. RESULTS
4.3.1 Drug sensitivity ofMCF7 cells in camptothecins
4.3.2. DNA topoisomerase I expression
4.3.3. DNA relaxation
4.3.4. Establishment ofMCF7/TPT cells
4.3.5. Drug sensitivity ofMCF7/TPT cells
FIGURES&TABLES
OTHERS

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Publication list
Chapter 2
1. Schneider, E., Horton, J.K., Yang, C.H., Nakagawa, M. & Cowan, K.H. (1994). Multidrug resistance-associated protein gene overexpression and reduced drug sensitivity of topoisomerase II in a human breast carcinoma MCF7 cell line selected for etoposide resistance. Cancer Research, 54, 152-8.
2. Yang, C.H., Cowan, K.H. and Schneider, E. (1993) Quantitative RT-PCR for DNA topoisomerase I, II-alpha, II-beta and mdr-1 in cell lines and tumor samples. Proceedings of AACR, 34, 10
Chapter 3
1. Yang, C.H., Wang, T.Y. and Chen, Y.C. (1998) Cytotoxicity of Arsenic Trioxide in Cancer Cell Lines. Proceedings of AACR, 39, 227.
2. Yang, C.H., Kuo M.L., Chen, J.C. and Chen, Y.C. (1999) Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells. British Journal of Cancer, 81(5),796-799.
Chapter 4
1. Yang, C.H., Horton, J.K., Cowan, K.H. and Schneider, E. (1995) Cross-resistance to camptothecin analogues in a mitoxantrone-resistant human breast carcinoma cell line is not due to DNA topoisomerase I alterations. Cancer Research, 55, 4004-4009
2. Yang, C.H., Cowan, K.H. and Schneider, E. (1996) Reselection of a mitoxantrone-resistant breast carcinoma cell line with mitoxantrone results in a parallel increase in cross-resistance to camptothecin analogues. Proceedings of AACR, 37,308.
3. Yang, C.H., Schneider, E., Kuo, M.L. and Chen, Y.C. Overexpression of breast cancer resistance gene in a topotecan-resistant human breast carcinoma cell line. (in revision)
Chapter 5
1. Yang, C.H., Cheng, A.L., Yeh, K.H., Yu, C.J., Lin, J.F. and Yang, P.C. (1999) High dose tamoxifen plus cisplatin and etoposide in advanced inoperable non-small cell lung cancer. Cancer,86,415-20