Expression of Proapoptotic Genes for Cancer Therapy

超出所提供的空间。毒性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之一。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，广泛适用，但毒性最小，这样治疗将更有效，毒性更小。本研究的目的是评估人类Bax和人类肿瘤坏死因子相关凋亡诱导配体（TRAIL）基因在人类端粒酶逆转录酶（hTERT）启动子驱动下表达时的治疗和毒性作用，并制定更好的治疗效果策略。待验证的假设是，Bax和/或TRAIL基因的高肿瘤特异性表达将消除肿瘤细胞，但不影响正常细胞的毒性作用。我们证明了TRAIL或Bax基因的直接转移在p53敏感和p53耐药的肿瘤细胞系中都能产生抗肿瘤作用，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，还构建了从hTERT启动子中表达Bax或TRAIL基因的单、双电子腺病毒载体，并对其功能进行了表征。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可能有效，而且毒性很小。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是否会产生耐药性，如果是，可能的机制是什么，以及这种耐药性能否被克服；2)将线粒体凋亡基因（如Bax）与膜凋亡基因（如TRAIL）结合可以提高治疗效果，特别是在对常规治疗有抗性的癌症中；3) hTERT- trail和hTERT- Bax载体可用于治疗体内化疗耐药的转移性肿瘤，以及治疗相关的毒性作用（如果有的话）。本提案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。它还将为癌细胞抵抗诱导凋亡的机制提供见解。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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 hTERT- Bax 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. PERFORMANCE SITE ========================================Section End===========================================