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Preliminary Study On The Expression Of Survivin And The Combination Therapy With It's Antisense Gene And Recombinant Fusion Protein Of Bladder Cancer

Posted on:2005-02-22Degree:DoctorType:Dissertation
Country:ChinaCandidate:X YanFull Text:PDF
GTID:1104360125467365Subject:Surgery
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Bladder carcinoma is the most common cancer of the genitourinary and the eighth most common cancer among Chinese man ,and its morbidity has been increasing during these years. In United States, bladder carcinoma is the fourth most common cancer in men and the eighth most common cancer in women, accounting for more than 54000 new cases and 11200 deaths every year. Treatment difficulty and poor prognosis usually ensue once muscle invasive tumors occur. Although the superficial bladder cancer can be treated with local transurethral resection followed by selective intravesical chemotherapy, there are still 10%~15% of superficial bladder cancer finally develop into the invasive bladder cancer. Despite considerable efforts to develop safe, reliable, noninvasive screening strategies for bladder cancer, the identification of a single predictive/prognostic marker of the disease has remained elusive. The development of bladder cancer involves many mechanisms, such as the activation of oncogene, the deactivation of anti-oncogene, angiogenesis,the activation of the invasive and metastatic factor and telomerase, and the enhancement of anti-apoptosis. This study was designed to investigate the development of bladder cancer on the point of apoptosis, and try to perform the experimental research about the effect of biotherapy combined with anti-apoptotic therapy on the bladder cancer cell in vitro. A novel modulator of the cell death/viability balance in cancer was recently identified as survivin, a member of the IAP family. Present during embryonic and fetal development, survivin was undetectable in normal adult tissues and became prominently overexpressed in various human cancers, including carcinomas of lung, stomach, colon, breast, and prostate as well as high-grade non-Hodgkin's lymphomas. These findings suggested that cancer cells return to a fetal pattern of survivin expression to enhance cell viability and thereby possibly also become able to overcome the cytotoxic effects of chemotherapeutic agents. Molecular antagonists of survivin including antisense or expression of a dominant negative mutant resulted in spontaneous apoptosis of cancer cells in vitro, and in vivo, and enhancement of chemotherapy-induced cell death. Transforming growth factor alpha (TGF alpha)-Pseudomonas exotoxin 40 (PE40) is a chimeric protein consisting of an N-terminal TGF alpha domain fused to a C-terminal 40-kDa segment of the Pseudomonas exotoxin A protein. TGF alpha-PE40 exhibits the receptor-binding activity of TGF alpha and the cell-killing activity of PE40. These properties make TGF alpha-PE40 an effective cytotoxic agent for cells that possess epidermal growth factor receptors (EGFR).Many studies have indicated that bladder cancer may overexpress the EGFR.We study the expression of survivin in bladder cancer at first.Then we investigate the inhibitory effect of the survivin antisense oligonucleotides on the proliferation of bladder cancer T24 cells. Finally,we try to maker sure whether the survivin antisense oligonucleotides may enhance the inhibitory effect of the TGF alpha-PE40 on bladder cancer T24 cells. Our ultimate purpose is to find a new approach to cure the terminal bladder cancer.Section One Immunohistochemical study of antiapoptotic factor suvivin in bladder transitional cell carcinomaObjective To investigate the expression of survivin in bladder transitional cell carcinoma and the relationship between it's expression and the stage, or grade, or relapse of bladder cancer. Materials and MethodsAll the 38 cases with bladder transitional cell carcinoma have pathological diagnosis. Tumor stage and grade were diagnosed according to the UICC clinical staging and WHO grading systems. Among 38 cases, 18 were Ta or T1, 9 T2, 7 T3 and 4 T4 tumors. Seven cases were G1, 18 G2 and 13 G3 tumors. Fourteen cases have the matched pairs of non-neoplastic tissue samples. Eight samples of normal bladder mucosa were from non-tumor cases. The method of immunohistochemistry was performed according to the protocol th...
Keywords/Search Tags:Bladder cancer, Apoptosis inhibitory factor, Survivin, Variant, TGFα-PE40, Targeted biotherapy, Antisense gene therapy
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