ANTICANCER CYTODIFFERENTIATION

描述（研究者摘要）：本申请旨在 进一步开发了一组新的细胞分化剂， 在治疗癌症和了解他们如何工作。在一个 与保罗·马克斯和理查德·里夫金德的合作 癌症研究所，在过去的15年里， 研究人员已经开发出了新的化合物， 癌细胞分化诱导剂，鼠红白血病和 也是人类白血病和结肠癌，以及其他癌症细胞类型， 体外 此外，最早的一个调查人员的化合物， 在I期和II期临床试验中很有希望。 调查人员 有一些化合物显示出一般的效果，而另一些化合物则是特定的 无论是对小鼠还是对人类细胞。 调查人员的新化合物 更有效约1,000倍，并且那些测试显示低毒性， 动物研究。 研究人员现在想设计出更有效的 化合物并了解它们是如何工作的。 后一种信息将是 在任何情况下，科学的宝贵部分，许多指导甚至设计 更好的药物 合作者有证据表明， 研究人员的化合物，但一个令人兴奋的线索是，他们发现， 激活蛋白激酶C（PKC）的次要同工酶。 但部分 研究人员活性化合物不作用于这种酶， 不同的功能;其他数据也表明，调查人员 发现了至少两种不同的诱导剂 的 研究者提出：（1）研究PKC酶激活的动力学， 包括由不同药物类别的成员竞争的研究 以及其他影响细胞分化的药物的研究，以测试 确实有强有力的证据表明，一些研究人员 通过激活这种酶来发挥作用。 调查人员还将研究物种 特异性，并试图确定这种酶的天然底物。 （二） 合成亲和柱和光亲和标记物， 各种药物类型，以协助分离和鉴定其 天然受体 (3)以制备新的细胞分化剂， 将具有更好的药用特性，基于结构/活性 研究人员建立的关系。

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.