THIOREDOXIN INHIBITION OF APOPTOSIS AND CANCER TREATMENT

描述：(申请人摘要) 细胞凋亡是细胞程序性死亡的一种形式，发生在对 基因损伤。它提供了最有效的机制，通过它 生物体可以保护自己免受癌症的侵袭。逃逸 从正常的凋亡过程来看，是癌细胞的一个标志。 对凋亡的抵抗也是癌细胞变得难治的一个原因 接受多种形式的化疗。信令的详细知识 介导细胞凋亡的途径及其在癌症中的变化 是理解人类起源和发展的基础 癌症。这些知识也可以为新战略提供基础。 为了预防和治疗癌症以及克服抗药性，通过 恢复癌细胞自身的死亡诱导途径的活性。 申请人已经发现了一种新的抗细胞凋亡基因trx，它编码 氧化还原蛋白硫氧还蛋白。他已经证明了TRX已经结束了- 在许多成人急性淋巴细胞白血病(ALL)中表达，其中 似乎与疾病的快速发展有关。他的 实验研究表明，淋巴球的稳定转染性 含Trx的细胞对自发和药物诱导的细胞凋亡的保护作用 并导致体内侵袭性肿瘤生长与减少相关 自发性细胞凋亡。因此，这些研究所依据的假设 基于，Trx是一种新的人类抗细胞凋亡基因，其过度表达 表达与侵袭性肿瘤生长和抗药性有关 化疗。申请人建议抑制硫氧还蛋白 信号转导提供了一种新的策略来直接抑制肿瘤生长和 以克服对化疗的耐药性。一组新型的血管紧张素转换酶抑制剂 硫氧还蛋白作为潜在的癌症化疗药物将被研究。 这些研究将集中在人类白血病上，但结果将是 适用于硫氧还蛋白过表达的其他形式的人类癌症- 表达。

DESCRIPTION: (Applicant's Abstract) Apoptosis is a form of programmed cell death that occurs in response to genetic damage. It offers the most potent mechanism by which the organism can protect itself against the development of cancer. Escape from the normal process of apoptosis is a hallmark of the cancer cell. Resistance to apoptosis is also a reason cancer cells become refractory to many forms of chemotherapy. A detailed knowledge of the signaling pathways that mediate apoptosis and how they become altered in cancer is fundamental to understanding the origins and development of human cancer. Such knowledge could also provide the basis for novel strategies to prevent and treat cancer and for overcoming drug resistance, by restoring the activity of the cancer cell's own death inducing pathways. The applicant has identified a new anti-apoptotic gene, trx, which codes for the redox protein thioredoxin. He has shown that trx is over- expressed in many adult acute lymphocytic leukemias (ALL) where it appears to be associated with rapidly progressing disease. His experimental studies have shown that the stable transfection of lymphoid cells with trx protects against spontaneous and drug-induced apoptosis and causes aggressive in vivo tumor growth associated with decreased spontaneous apoptosis. Thus, the hypothesis upon which these studies are based is that trx is a new human anti-apoptosis gene whose over- expression is associated with aggressive tumor growth and resistance to chemotherapy. The applicant proposes that inhibiting thioredoxin signaling offers a novel strategy to directly inhibit tumor growth and to overcome resistance to chemotherapy. A group of novel inhibitors of thioredoxin as potential cancer chemotherpeutic agents will be studied. These studies will focus on human leukemia, but the findings will be applicable to other forms of human cancer where thioredoxin is over- expressed.