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)： 毒副作用是大多数抗癌疗法的主要缺点，也是患者最担心的问题。因此，我们的目标是开发基于生物作用机制的癌症治疗技术，这种技术具有广泛的适用性，但毒性最小，从而使治疗更有效，毒性更低。本研究的目的是评价人bax和人肿瘤坏死因子相关的凋亡诱导配体(TRAIL)基因在人端粒酶逆转录酶(HTERT)启动子驱动下表达时的治疗和毒性作用，并开发更好的策略以获得最佳的治疗效果。需要检验的假设是，Bax和/或TRAIL基因的高肿瘤特异性表达将消除肿瘤细胞，但不会对正常细胞产生毒性影响。我们证明，直接转移TRAIL或Bax基因可以在p53敏感和耐药的肿瘤细胞中产生抗肿瘤作用，并且hTERT启动子能够在不影响其抗肿瘤活性的情况下阻止Bax或TRAIL基因的毒性作用。此外，还构建了表达hTERT启动子Bax或TRAIL基因的单双顺反子腺病毒载体，并对其功能进行了鉴定。正在进行的研究的初步数据表明，这些载体在治疗癌症方面潜在有效，而且毒性最小。然而，目前尚不清楚的是1)。对腺载体介导的促凋亡基因治疗产生耐药性，如果是的话，可能的机制是什么，耐药性可以被克服；2)将线粒体凋亡基因(如Bax)与膜凋亡基因(如TRAIL)相结合，可提高治疗效果，特别是在对常规治疗耐药的癌症中；以及3)。HTERT-TRAIL和hTERTBax载体可用于体内治疗对化疗耐药的已建立的转移瘤，以及与治疗相关的毒性作用(如果有的话)。这项提议旨在解决这些未知问题。拟议研究的成功将导致难治性转移性疾病的新疗法。它还将提供对癌细胞抗凋亡诱导的机制的洞察。