PROBING MDR & MRP WITH SIMPLE COMPOUNDS & ANTHRACYCLINES

多药耐药(MDR)存在于多种人类肿瘤中 细胞，似乎在癌症的失败中起着重要的作用 化疗。克服DDR的关键是理解它是如何 识别大量不同的化合物，并积极地将它们排出体外。 由于这些化合物中的大多数是复杂的，使结构具有功能 分析困难的一系列非常简单的有机化合物 在亲脂性上系统不同的(吡啶类和金刚烷类) 通过逐步加长它们的烷基链长， 合成用于研究多药耐药。使用这些化合物，一个单一的芳香族化合物 环和大于4个碳的最小脂肪链长度为 被发现是识别MDR所必需的。目前的提案将 使用这些简单的化合物来进一步定义化学成分 这是识别和调节这种形式的抗性所必需的。 最近，一种多药耐药相关蛋白(MRP)，具有 类似于MDR的传输特性和阻力分布， 已经在人类肿瘤样本中被证实是正确的。初步证据 表明我们合成的一系列简单化合物中没有一个 并被发现被MDR认可，是对这一新的 简单的复合导数。因此，在这份提案中，我们计划使用 进一步探讨化学要求的简单化合物 识别MDR，并将其与MRP的识别区分开来。这些 研究应该为合理的设计提供坚实的基础 新的，更好地使用已知的更复杂的化合物，以克服 临床确定的耐药机制。越复杂 化合物将包括一系列我们 合成的，在化学电荷上有系统的不同 亲油性。在此基础上增加了MDR和MRP转染系 建议确认和进一步确定我们的初步调查结果 用我们培养的MDR和MRP细胞株通过暴露获得 到细胞毒性药物。生长抑制研究与罗丹明123 将进行保留分析以分析生物 这些过程的运作。药物累积研究： 这些抗性机制的修饰物将被用来 进一步研究这些过程。光亲和力分析将 补充我们的研究，以更好地了解这些 有两种抵抗机制。

Multi-drug resistance (MDR) is found in a variety of human tumor cells and appears to play a significant role in the failure of cancer chemotherapy. A key to overcoming DDR is to understand how it recognizes a number of diverse compounds and actively effluxes them. Since most of these compounds are complex, making structure function analyses difficult, a series of very simple organic compounds (pyridiniums and guanidiniums) differing systematically in lipophilicity by step-wise lengthening of their alkyl chain lengths, were synthesized to study MDR. Using these compounds, a single aromatic ring and a minimal aliphatic chain length greater than 4 carbons were found to be necessary for MDR recognition. The current proposal will use these simple compounds to further define the chemical components necessary for recognition and modulation of this form of resistance. Recently, a multi-drug resistance related protein (MRP), with transport properties and resistance profiles similar to that of MDR, has been sound in human tumor samples. Preliminary evidence indicates that none of the series of simple compounds we synthesized and found to be recognized by MDR, are recognition of this new simple compound derivative. Thus, in this proposal we plan to use the simple compounds to further explore the chemical requirements for MDR recognition and distinguish them from those of MRP. These studies should provide a solid foundation for the rational design of new, and better use of known more complex compounds, to overcome thee clinically identified mechanisms of resistance. The more complex compounds will include a series of anthracycline analogs that we synthesized which differ systematically in chemical charge and lipophilicity. MDR and MRP transfectant lines are added to this proposal to confirm and further characterize our initial findings obtained with the MDR and MRP cell lines we developed by exposure to cytotoxic drugs. Growth inhibition studies and rhodamine 123 retention assays will be performed to analyze the biological functioning of these processes. Drug accumulation studies with modifiers of each of these mechanisms of resistance will be used to further investigate these processes. Photo affinity assays will complement our studies to better understand the specificities of these two mechanisms of resistance.