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.
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