Expression of Proapoptotic Genes for Cancer Therapy

用于癌症治疗的促凋亡基因的表达

• 批准号: 7064270
• 负责人: BINGLIANG FANG
• 金额: $ 32.81万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064270
• 关键词: Expression; Proapoptotic; Genes; Cancer; Therapy

DESCRIPTION (provided by applicant): Toxic effects are the major drawback of most anticancer therapeutics and are in the top list of patients' worries. Therefore, our goal is to develop technology for cancer treatment that is based on biological mechanisms of action, broadly applicable, and yet minimally toxic so that the treatment will be more effective and less toxic. The goals of the proposed studies are to evaluate the therapeutic and toxic effects of human Bax and human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes when their expression is driven by the human telomerase reverse transcriptase (hTERT) promoter and to develop better strategies for optimal therapeutic effects. The hypothesis to be tested is that the high tumor-specific expression of the Bax and/or TRAIL genes will eliminate tumor cells but spare normal cells their toxic effects. We demonstrated that direct transfer of the TRAIL or Bax gene resulted in antitumor effects in both p53-sensitive and p53-resistant tumor lines and that hTERT promoter was able to prevent toxic effects of the Bax or TRAIL gene without compromising their antitumor activities. Moreover, single, bicistronic adenoviral vectors expressing the Bax or TRAIL gene from the hTERT promoter were also constructed and their functionality characterized. Preliminary data from studies in progress have shown that these vectors are potentially effective in the treatment of cancers and that they are minimally toxic. Yet, what remains unknown is whether 1). resistance develops to adenovector-mediated proapoptotic gene therapy and, if so, what the possible mechanisms are and the resistance can be overcome the resistance; 2). combining mitochondrion apoptotic genes (such as Bax) with membrane-apoptotic genes (such as TRAIL) improves therapeutic effects, especially in cancers that are resistant to conventional therapy; and 3). hTERT-TRAIL and hTERTBax vectors can be used to treat established metastatic tumors that are resistant to chemotherapy in vivo and what the treatment-related toxic effects are, if any. This proposal is designed to address these unknowns. Success of the proposed studies will lead to new therapeutics for refractory metastatic disease. It will also provide insight into mechanisms of resistance to apoptosis induction in cancer cells.

描述（由申请人提供）： 有毒作用是大多数抗癌治疗剂的主要缺点，并且是患者担心的首要局部缺点。因此，我们的目标是开发基于生物学作用机制，广泛适用，但毒性极低，以便治疗将更有效且毒性较小。拟议的研究的目标是评估人类巴克斯和人类肿瘤坏死因子相关凋亡诱导配体（TRAIL）基因的治疗和毒性作用，当更好的最佳治疗作用策略。要检验的假设是，BAX和/或TRAR基因的高肿瘤特异性表达将消除肿瘤细胞，但要避免正常细胞的毒性作用。我们证明了径径或BAX基因的直接转移导致p53敏感性和p53耐药性肿瘤线产生抗肿瘤作用，并且HTERT启动子能够防止Bax或Trail Gene的毒性作用而不会损害其抗肿瘤活性。此外，还构建了表达来自HTERT启动子的BAX或TRAIL基因的单一腺病毒载体，其功能性也表征了。正在进行的研究中的初步数据表明，这些载体可能在治疗癌症的治疗中有效，并且它们的毒性极低。但是，尚不清楚的是1）。耐药性会发展为腺窝介导的促凋亡基因治疗，如果是的，则可能是什么可能的机制，并且可以克服耐药性； 2）。线粒体凋亡基因（例如BAX）与膜 - 凋亡基因（例如TRAIL）相结合可改善治疗作用，尤其是在对常规疗法抗性的癌症中；和3）。 HTERT-TRAIL和HTERTBAX载体可用于治疗已建立的转移性肿瘤，这些转移性肿瘤对体内的化学疗法有抗性以及与治疗相关的毒性作用是什么（如果有）。该建议旨在解决这些未知数。拟议的研究的成功将导致新的耐火转移性疾病的治疗疗法。它还将洞悉癌细胞抗凋亡诱导的抗性机制。