POLYAMINES AS A POTENTIAL CHEMOTHERAPEUTIC TARGET

该计划的总体目标是利用现有的多胺 抑制剂和类似物，以研究多胺的生物合成，代谢和 在肿瘤细胞类型中起作用，同时， 鉴定和评价潜在化疗独特靶位点 干预 新的多胺类似物的最近可用性和 抑制剂和新的生物系统在这一计划提供了 新的机会，研究多胺生物学的各个方面。 其中包括使用新表征的S-抑制剂， 腺苷甲硫氨酸脱羧酶以消耗或选择性调节和 控制所有三个细胞内多胺库。 这些新线索将 用于：（1）表征单个多胺的需求， 细胞生长和分化;（2）研究 单个多胺库和多胺运输的调节 系统和某些生物合成酶;（3）检查的意义 多胺生物合成的副产物5 '-脱氧-5'- 甲硫腺苷对细胞生长和分化的影响;（4）研究 完整细胞中多胺-DNA相互作用;（5）检查 癌基因表达作为敏感性决定因素的作用 多胺类似物和抑制剂，以及（f）评估 作为化疗靶点的特定酶和机制。 虽然 多样性，提出的研究是统一的共同目标下，这 在几乎所有情况下，项目的可行性都得到了进展的支持 和/或初步数据。

The overall objective of this Program is to utilize available polyamine inhibitors and analogs to study polyamine biosynthesis, metabolism and function as it occurs in neoplastic cell types and, at the same time, to identify and evaluate unique target sites for potential chemotherapeutic intervention. The recent availability of novel polyamine analogs and inhibitors and novel biological systems within this Program has afforded new opportunities to study various aspects of polyamine biology. Included among these is the use of a newly characterized inhibitor of S- adenosylmethionine decarboxylase to deplete or selectively modulate and control all three intracellular polyamine pools. These new leads will be used to: (1) characterized the individual polyamine requirement for cell growth and differentiation; (2) study the relationship between individual polyamine pools and regulation of the polyamine transport system and certain biosynthetic enzymes; (3) examine the significance of the by-product of polyamine biosynthesis, 5'-deoxy-5'- methylthioadenosine, to cell growth and differentiation; (4) study polyamine-DNA interactions in the context of intact cells; (5) examine the role of oncogene expression as a determinant of sensitivity to polyamine analogs and inhibitors and (f) evaluate the potential of specific enzymes and mechanisms as chemotherapeutic targets. Although diverse, the proposed research is unified under the common goal of this Program and, in nearly all cases, feasibility is supported by progress and/or preliminary data.