PROBING MDR & MRP WITH SIMPLE COMPOUNDS & ANTHRACYCLINES

多药耐药（Multi-drug resistance，MDR）存在于多种人类肿瘤中 细胞，似乎在癌症的失败中发挥重要作用， 化疗 克服DDR的一个关键是了解它是如何 识别许多不同的化合物并主动排出它们。 由于大多数化合物都很复杂， 分析一系列非常简单的有机化合物 （吡啶鎓和胍鎓）亲脂性系统不同 通过逐步延长它们的烷基链长度， 合成以研究MDR。 使用这些化合物， 环和大于4个碳的最小脂族链长度是 被认为是MDR识别所必需的。 目前的提案将 用这些简单的化合物来进一步定义化学成分 识别和调节这种形式的阻力所必需的。 最近，多药耐药相关蛋白（MRP）， 与MDR相似的转运特性和抗性曲线， 在人类肿瘤样本中是可行的。 初步证据 表明我们合成的一系列简单化合物 并被MDR所识别，是对这种新的 简单复合衍生物 因此，在本提案中，我们计划使用 简单的化合物，以进一步探讨化学要求， MDR的识别，并与MRP进行区分. 这些 研究应提供一个坚实的基础，为合理的设计， 新的，更好地利用已知的更复杂的化合物，以克服 三种临床鉴定的耐药机制。越复杂 化合物将包括一系列蒽环类类似物， 所合成的化合物在化学电荷上系统地不同， 亲脂性 将MDR和MRP转染子系添加到其中， 确认和进一步说明我们初步调查结果的建议 用我们通过暴露于 到细胞毒性药物。 生长抑制研究和罗丹明123 将进行保留测定以分析生物学特性。 这些过程的运作。 药物蓄积研究， 这些抗性机制中的每一种的改性剂将用于 进一步研究这些过程。 光亲和测定将 补充我们的研究，以更好地了解这些特殊性， 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.