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研究生:謝嘉興
研究生(外文):Gia-Shing Shieh
論文名稱:利用端粒酶反轉錄酶調控腺病毒的基因治療膀胱癌
論文名稱(外文):Telomerase-dependent adenovirus-mediated gene therapy in a syngeneic bladder tumor model
指導教授:蔡宗欣蔡宗欣引用關係吳昭良
指導教授(外文):Tzong-Shin TzaiChao-Liang Wu
學位類別:博士
校院名稱:國立成功大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:95
語文別:中文
論文頁數:87
中文關鍵詞:溶瘤腺病毒膀胱腫瘤腺病毒端粒酶自殺基因
外文關鍵詞:bladder tumoradenovirussuicide geneoncolytic adenovirustelomerase
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在人類的惡性腫瘤裡,大部分癌細胞都會表現人類端粒酶反轉錄酶 (human telomerase reverse transcriptase, hTERT),但是在正常細胞中則無此表現,因此許多文獻報告利用hTERT 啟動子 (promoter) 調控治療性基因表現以治療人類的惡性腫瘤。首先我們建構由hTERT promoter 調控cytosine deaminase (CD)自殺基因的腺病毒 (Ad-hTERT-CD)並且結合低劑量的etoposide治療膀胱腫瘤,我們發現在5-fluorocytosine (5-FC)治療下,低劑量etoposide能增加Ad-hTERT-CD對膀胱癌細胞的治療效果,但是對於正常細胞則無毒殺作用。其機轉包括低劑量etoposide治療下,膀胱癌細胞的缺氧調控因子hypoxia-inducible factor-1 (HIF-1) 會被活化,接著促使hTERT promoter活性上升。相反地,低劑量etoposide活化正常細胞的p53因子,促使hTERT promoter活性下降。另外,低劑量etoposide治療下,細胞表面的coxsackie-adenovirus receptor (CAR)表現會上升進而增加腺病毒的感染效果。在動物實驗中,結合Ad-hTERT-CD/5-FC及低劑量etoposide可抑制膀胱腫瘤生長,使75%腫瘤完全消失,並且增加腫瘤中的免疫細胞CD4+及CD8+的數量。因此結合Ad-hTERT-CD/5-FC及低劑量etoposide能更有效地治療膀胱惡性腫瘤。接著我們利用hTERT promoter驅動腺病毒的E1A基因,製造出E1B-55kD缺失的溶瘤腺病毒 (Ad5GS1)來治療膀胱腫瘤,結果Ad5GS1能有效地毒殺人類及老鼠的膀胱癌細胞,但是對於表現telomerase 的正常細胞 (包括老鼠胚胎幹細胞)則無毒殺效果。在動物實驗中,Ad5GS1能有效抑制膀胱腫瘤生長及增加老鼠的存活率,並且治療成效更優於只改造E1B-55kD缺失的溶瘤腺病毒 (Ad5WS1)。進一步地,我們結合表皮成長因素感受器 epidermal growth factor receptor (EGFR)抑制劑 Iressa及Ad5GS1治療膀胱癌細胞,結果我們發現在Iressa治療無效的膀胱腫瘤細胞中,Iressa會活化hTERT promoter活性,並且增加Ad5GS1的治療成果。因為大部分的人類惡性腫瘤都會表現telomerase,因此結合藥物及hTERT promoter調控的基因治療將能更有效的治療人類惡性腫瘤。
The promoter of human telomearse reverse transcriptase (hTERT) is inactive in normal cells, but active in the majority of cancers. The hTERT promoter can selectively drive transgene expression in telomerase-positive cancers. Here we evaluated the combination therapy of adenoviral vector Ad-hTERT-CD encoding E. Coli cytosine deaminase (CD) drived by the hTERT promoter and low-dose etoposide (0.1 μg/mL) for treating bladder cancer. The results showed that Ad-hTERT-CD conferred sensitivity to 5-fluorocytosine (5-FC) in bladder cancer cells, which could be enhanced by etoposide treatment, but not in normal cells. The up-regulated hTERT promoter was correlated with the expression of hypoxia-inducible factor (HIF)-1α. By contrast, etoposide activated p53 and down-regulated hTERT promoter activity in normal cells. Etoposide also increased adenoviral infection via enhancement of coxsackie-adenovirus receptor (CAR) expression on bladder cancer and normal cells. The combined therapy of Ad-hTERT-CD (109 plaque-forming units)/5-FC (200 mg/kg) with etoposide (2 mg/kg) synergistically suppressed tumor growth and prolonged survival in mice bearing syngeneic MBT-2 bladder tumors. This combination therapy induced complete tumor regression in 75 % of tumor-bearing mice. Furthermore, increased infiltrating CD4+ and CD8+ T cells and necrosis within the tumors were found in mice receiving combination therapy of Ad-hTERT-CD and etoposide compared with those treated with either treatment alone. Thus, the combination therapy may be an appealing therapeutic intervention for bladder cancers. In adenoviral vector system, conditionally replicating adenoviruses (CRAds), which can induce cytolysis of infected tumor cells and spread to surrounding cells, can provide better antitumor efficacy than non-replicating groups. Iressa is a selective tyrosine kinase inhibitor of EGFR, which is overexpressed in majority of human bladder cancers, to block tumor cell proliferation, survival and progression. We hypothesized that the combined therapy of Iressa and an E1B-55kD-deleted CRAd, designed Ad5GS1 which expressed intact E1A driven by hTERT promoter, exerted tumor-specific oncolysis. Ad5GS1 caused severe cytolysis in telomerase-positive human and murine bladder cancer cells, which could be enhanced by Iressa, whereas it was severely attenuated in telomerase-positive normal cells, including murine nontransformed, immortalized fibroblasts and embryonic stem cells. Most notably, after Ad5GS1 infection hTERT promoter was continuously up-regulated in murine bladder cancer cells with mutant p53. The up-regulation of hTERT promoter activity was correlated with the dosage of E1A, which was the adenoviral early gene driven by hTERT promoter. Iressa also up-regulated hTERT promoter activity in Iressa-resistant bladder cancer cells. Ad5GS1 exhibited higher oncolytic activities than an E1B-55 kD-deleted adenovirus driven by the E1A promoter in both in vitro and in vivo studies. Intratumoral administration of Ad5GS1 significantly retarded tumor growth and prolonged the survival time in immunocompetent mice bearing murine bladder tumors. The replication of Ad5GS1 was detectable in tumors for at least 15 days after treatment. Our results suggest that oncolytic effects of Ad5GS1 in telomerase-positive bladder cancer cells provides safety features for tumor-selective killing and yields a therapeutic benefit in the syngeneic murine tumor model, which is relevant to clinical settings. Furthermore, Iressa up-regulated the hTERT promoter activity to enhance the cytolytic efficacy of Ad5GS1 system. Because a majority of human tumors exhibit high telomerase activity, the combination therapy of chemotherapeutic agent and hTERT promoter-driven gene therapy may be applicable to a broad spectrum of cancers.
Chinese abstract 3
Abstract 5
Content 8
Figure content 11
Acknowledgement 12
Introduction
A. Biology of human adenovirus 14
B. Adenoviral vector for therapy 15
C. Oncolytic adnovirus 15
D. Telomerase and telomerase reverse transcriptase promoter 16
E. Suicide gene therapy-Escherichia Coli cytosine deaminase (CD) 17
F. Iressa and etoposide 18
Specific aims
Part I. The therapeutic effect of Ad-hTERT-CD/5-FC system combined with 20
low-dose etoposide for bladder cancers
Part II. Iressa enhances oncolytic therapy of E1B-55kD-deleted 21
replication-competent adenovirus driven by hTERT promoter in
syngeneic bladder cancer models
Materials and Methods
Part I
Cells, mice and chemotherapeutic agents 22
Analysis of hTERT promoter activity and p53 and HIF-1 22
transcriptional activities
Construction of Ad-hTERT-CD adenoviral vector 24
In vitro cell viability assay 24
Western blot analysis 25
Flow cytometric analysis of CAR and integrin expressions on bladder cancer 25
cells after etoposide treatment
Determination of cell susceptibility to infection by adenovirus 25
Animal studies 26
Histological and immunohistochemical analyses 26
Statistical analysis 27
Part II
Cells, mice and Iressa 28
Construction of oncolytic adenoviruses 28
Analyses of p53 mutation and transcriptional activity, and hTERT promoter 29
activity
Determination of susceptibility of various cell lines to adenoviral infection 30
Assays of CPE, cell viability and viral replication 30
Animal studies 31
Immunohistochemistry 32
Statistical analysis 32
Results
Part I:
Ad-hTERT-CD/5-FC treatment suppressed tumor growth and prolonged 33
survival in mice bearing MBT-2 tumors
Low-dose etoposide enhanced transgene expression driven by the hTERT 34
promoter through upregulation of HIF-1a expression in murine bladder
model
Etoposide enhanced adenovirus infection through upregulation of CAR but 35
not of avb3 and avb5 integrins on bladder cancer cells
Ad-hTERT-CD/5-FC in combination with etoposide enhanced 5-FC 36
sensitivity to human and murine bladder cancer cells but decreased
cytotoxicity to normal cells
Ad-hTERT-CD/5-FC and etoposide synergistically suppressed tumor 37
growth and prolonged survival in mice bearing syngeneic MBT-2 tumors
Part II:
Detection of p53 dysfunction in MBT-2-CF1 cells 39
High promoter activity of hTERT in MBT-2-CF1 and murine embryonic 40
stem cells
Similar susceptibility of human and murine bladder cancer cells to 40
adenoviral infection
Ad5GS1 induced cytotoxic activity and viral replication in 41
telomerase-positive bladder cancer cells
Ad5GS1-induced regulation of hTERT promoter activity correlated with 42
E1A expression
Retardation of tumor growth and prolongation in survival time of the 43
immunocompetent mice bearing bladder tumor by Ad5GS1 treatment
Transient replication of Ad5GS1 in immunocompetent murine bladder 44
tumor models
Iressa up-regulated the hTERT promoter to enhance cytolytic activity of 44
Ad5GS1 in various bladder cancers
Discussion
Part I 46
Part II 51
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