There is no effective treatment for metastatic prostatic cancer which has become refractory to hormone therapy. Traditional chemotherapeutic agents alone or in combination have failed to make significant impact on this disease. Novel approaches to effectively treat hormone-resistant prostate cancer must be developed. Pathologists have traditionally recognized cancer cells in pathologic and cytologic specimens based on altered nuclear morphology and abnormal chromatin patterns. It is now recognized that these altered nuclear parameters are controlled to a large extent by the nuclear matrix. The nuclear matrix is the RNA-protein network of the nucleus that provides structural support to the nucleus and DNA and which plays important roles in DNA replication, RNA processing, and gene expression. The importance of the nuclear matrix in understanding the cancer process and in the treatment of cancer has not been well recognized. It has now been demonstrated that the nuclear matrix is altered in cancer cells and is intimately involved in mechanisms of DNA synthesis inhibition by chemotherapeutic agents. The goal of this proposal is to develop a laboratory and clinical program that investigates nuclear matrix structure as a target for prostate cancer chemotherapy. Agents which alter nuclear matrix structure will be investigated to determine cytotoxicity as well as pathologically and biochemically defined their mechanisms of action. Promising agents which alter nuclear matrix-DNA interactions will be further tested in both in vitro and in vivo prostate adenocarcinoma cytotoxicity assays. The ultimate goal of this proposal is to apply the results of these laboratory investigations to the treatment of hormone-refractory prostate cancer. The first clinical trial based on this research will soon begin to accrue patients.
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