肺癌治療之新穎策略的研發

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 醫學院 > 癌症生物學研究所 > 研究計畫 > Item 310903500/44659

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题名:	肺癌治療之新穎策略的研發
作者:	洪明奇(Mien-Chie Hung);李龍緣(Long-Yuan Li)
贡献者:	醫學院癌症生物學研究所;中國附醫院長室
关键词:	肺癌治療;基因治療;lung cancer treatment;gene therapy
日期:	2011-04-30
上传时间:	2012-06-15 11:43:24 (UTC+8)
摘要:	血管內皮抑制素(endostatin），是已被清楚了解的血管內皮新生的抑制劑，在美國許多臨床試驗中證明具有阻斷新生血管的功能，並在中國被認可為抗癌藥。然而，血管內皮抑制素的功能僅只於抑制癌細胞的生長，呈現細胞穩定性(cytostatic)，而非達到殺死癌細胞的細胞毒殺(cytotoxic)作用。我們提出的假設是一個同時具備癌細胞專一性的細胞穩定性及細胞毒殺活性的藥物應可成為更有療效的抗癌藥。為了試驗該假設的可行性及發展成有效的乳癌用藥，我們初步的研究結果顯示：結合血管內皮抑制素及胞嘧啶脫氨?(cytosine deaminase)的融合蛋白質，Endo-CD，不但具有血管內皮抑制素可辨認新生血管茂盛的腫瘤處，且帶有細胞毒殺作用的胞嘧啶脫氨?可將無害的前驅藥5-氟胞嘧啶（5-fluorocytosine, 5-FC）轉變為細胞毒素氟嘧啶二酮（5-fluorouracil, 5-FU）。此血管內皮抑制素-胞嘧啶脫氨?的融合蛋白質(Endo-CD)具有比個別血管內皮抑制素或胞嘧啶脫氨?有更強的抑制腫瘤的生長及延長動物存活時間的效果。此外，我們已發展出Bik (Bcl2 interacting killer)的突變物，稱為BikDD，是將其蘇氨酸三十三(threonine)及絲氨酸三十五 (serine 35)的位置改成冬氨酸(aspartic acid)，以模擬此兩個氨基酸磷酸化的狀態。此突變物BikDD具有比野生型還強的抗癌能力。我們的初步結果顯示Endo-CD及BikDD可當作癌症治療所用的治療基因。我們的目標為發展出毒性更小且更具治療潛力的藥物於肺癌治療上。在發展基因治療法時，為確保治療用基因能專一性的表現於癌細胞目標物上，我們最近也發展出一套癌細胞專一性高量表達系統，VISA (VP16-Gal4-WPRE integrated systemic amplifier) 系統，可將攜帶的基因，如BikDD選擇性的表現於癌細胞上而不表現於正常細胞內，並增強癌細胞專一性的啟動子效果而不影響其對癌細胞的專一性。此治療策略已成功地運用在胰臟癌動物治療模式上。我們未發表的結果指出此治療策略在乳癌動物模式也成功。因此，我們想延伸此VISA系統並結合肺癌專一的啟動子(promoter)於肺癌細胞株及肺癌動物模式上測試。現在，我們有兩個候選啟動子，claudin 4及survivin，兩者皆高表現於肺癌細胞株內。由於Endo-CD及BikDD可當作有效的治療基因，我們將比較兩者個別的治療效果，及合併兩個基因於同一個載體上使其能同時表現於癌細胞中並測試其治療效果。由Claudin 4-VISA或Survivin-VISA所啟動的治療載體將在肺癌動物模式上測試其治療效果。具有高度癌細胞抑制能力並對動物低毒害的治療載體，將可後續發展成進入臨床試驗的抗癌藥物。 Endostatin, a well-characterized endogenous angiogenesis inhibitor, selectively targets neovascular endothelial cells and has been tested in multiple clinical trials in U.S. and approved as an anti-cancer drug in China. However, endostatin exerts its function by inhibiting growth of cancer cells instead of killing them, i.e. “cytostatic” rather than “cytotoxic”. We hypothesize that a dual function agent harboring both tumor-specific cytostatic and cytotoxic activities may be a more effective anti-cancer drug. We have obtained preliminary results to show that a fusion protein endostatin-cytosine deaminase (Endo-CD) containing “cytostatic” endostatin, which retains its tumor targeting ability and a “cytotoxic” protein--cytosine deaminase (CD) that can convert the pro-drug 5-fluorocytosine (5-FC) into the chemotherapeutic drug 5-fluorouracil (5-FU), exerts much stronger tumor growth suppression and increases mean survival time than treatments of either endostatin or CD alone. In addition, we have developed a Bik (Bcl2 interacting killer) mutant, BikDD in which threonine 33 and/or serine 35 were changed to aspartic acid to mimic the phosphorylation at these two residues, and found the mutant’s anti-cancer activity more potent than wild type’s. Our preliminary results suggest that both Endo-CD and BikDD may serve as potent therapeutic genes for cancer treatment. Our goal is to develop a more effective anti-cancer drug with minimal toxicity for lung cancer gene therapy. To ensure cancer-specific targeting while developing gene therapy, we have recently developed a highly cancer-specific expression vector, VISA (VP16-Gal4-WPRE integrated systemic amplifier), which allows a therapeutic gene such as BikDD to selectively kill cancer cells but have virtually no effect in normal cells. This approach has been successfully shown in pancreatic cancer animal models. Our unpublished data also indicated that this approach works in breast cancer animal models. Thus, we intend to extend this VISA vector combining with lung cancer-specific promoter to test in lung cancer cell lines in cell culture and lung cancer animal models. Currently, we have two promoter candidates, claudin 4 and survivin which are highly expressed in lung cancer cell lines. Since both Endo-CD and BikDD have been shown to be effective therapeutic genes, we will compare their therapeutic efficacy individually and also test combination therapy by expression of both Endo-CD and BikDD in the same plasmid DNA. The therapeutic plasmids driven by Claudin 4-VISA or Survivin-VISA will be examined for their therapeutic efficacy in orthotopic lung cancer models. The best therapeutic plasmid with high tumor suppression activity and low toxicity in animals will justify for further development of a novel therapy for lung cancer in future clinical trials.
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