ANTICANCER CYTODIFFERENTIATION

描述(调查人员摘要)：此应用程序的目标是 进一步开发一组新的细胞分化剂， 对癌症的治疗和了解它们是如何工作的很有用。 与斯隆-凯特琳的保罗·马克斯和理查德·里夫金德合作 癌症研究所，在过去的15年里， 研究人员开发了一种新的化合物，这种化合物具有 癌细胞的分化诱导剂，小鼠红白血病和 人类白血病和结肠癌，以及其他类型的癌细胞 体外培养。此外，研究人员最早的化合物之一已经 在I期和II期临床试验中前景看好。调查人员 有表现出一般影响的化合物和其他特定的化合物 无论是对小鼠细胞还是对人类细胞。调查人员的新化合物是 效力提高约1000倍，测试结果显示， 动物研究。调查人员现在想要设计出更有效的 并学习它们的工作原理。后一信息将是 在任何情况下，科学的有价值的部分，和许多指导设计甚至 更好的药物。 合作者有证据证明这种病毒具有多种生物学效应。 研究人员的化合物，但一个令人兴奋的线索是发现它们 激活蛋白激酶C(PKC)的一个次要同工酶。然而，一些 研究人员活性化合物不作用于这种酶，必须有一个 不同的功能；其他数据也表明，调查人员 发现了至少两类不同的诱导剂。这个 研究人员提出：(1)对PKC酶的激活进行动力学研究， 包括不同药物类别成员的竞争研究 以及对其他影响细胞分化的因素的研究，以测试是否 确实有强有力的证据表明，一些调查人员合成了 通过激活这种酶来工作。研究人员还将研究物种 并尝试鉴定该酶的天然底物。(2) 合成亲和色谱柱和光亲和标记 各种药物类型，以帮助分离和鉴定其 天然受体。(3)制备新的细胞分化剂 将在结构/活性的基础上具有更好的药用性能 调查人员已经建立了关系。

DESCRIPTION (Investigator's Abstract): This application is aimed at further developing a new group of cytodifferentiating agents that are useful in the treatment of cancer and learning how they work.In a collaboration with Paul Marks and Richard Rifkind of the Sloan-Kettering Institute for Cancer Research that extends over the past 15 years, the investigators have developed novel compounds that act as effective inducers of differentiation in cancer cells, of murine erythroleukemia and also of human leukemia and colon cancer, and other cancer cell types in vitro. In addition, the earliest one of the investigators' compounds has been promising in Phase I and Phase II clinical trials. The investigators have compounds that show general effects and others that are specific either for mouse or for human cells. The investigators' new compound are more potent by about 1,000-fold, and those tested show low toxicity in animal studies. The investigators now want to design even more effective compounds and learn how they work. This latter information will be a valuable part of science in any case, and many guide the design of even better drugs. The collaborators have evidence for a variety of biological effects of the investigator's compounds, but an exciting lead is the finding that they activate a minor isozyme of protein kinase C (PKC). However, some of the investigators active compounds do not act on this enzyme and must have a different function; other data also indicates that the investigators have discovered at least two different classes of inducing agents. The investigators propose: (1) to study the PKC enzyme activation kinetically, including studies with competition by members of the different drug classes and studies with other agents that affect cytodifferentiation, to test if there is indeed strong evidence that some of the investigators compounds work by activating this enzyme. The investigators will also study species specificity and try to identify the natural substrate of this enzyme. (2) to synthesize affinity columns and photoaffinity labels based on the various drug types, to assist in the isolation and identification of their natural receptors. (3) to prepare new cytodifferentiating agents that will have better medicinal properties, building on the structure/activity relationships the investigators have developed.