ANTITUMOR MECHANISM OF DIARYLSULFONYLURE

描述：(主要研究人员)二芳基磺酰脲(DSU)具有 已被确定为一类新的抗肿瘤药物。DSU展示了广泛的 抗实体瘤活性谱，无毒副作用 增殖的正常组织，这通常与其他 传统的抗肿瘤药物。此外，DSU没有表现出交叉- 对其他抗肿瘤药物具有耐药性，不属于P- 糖蛋白介导的多药耐药(MDR)表型 在治疗抗电肿瘤方面具有巨大潜力 抗肿瘤药物。尽管付出了无数努力，但其抗肿瘤机制 的比例仍未定义。但很明显，与其他国家不同 传统的抗肿瘤药物，DSU不抑制DNA的合成， RNA或蛋白质，没有表现出对细胞周期的依赖，这表明它们 通过一种潜在的独特和新颖的机制采取行动。 我们认为DSU的抗肿瘤活性是有贡献的(或 部分由谷胱甘肽还原酶(GR)抑制所致 阿司匹林的潜在代谢物谷胱甘肽结合物对肿瘤细胞的抑制作用。GR 是细胞活力的重要酶。我们的初步结果 证明了一种与谷胱甘肽结合物相关的GR抑制剂 抑制对DSU敏感的肿瘤细胞生长的效力是 母体毒品。拟议中的研究旨在检验这一假设。 和磺胺甲醚的代表性化合物，将被用于 检验这一假设。这项研究将涉及谷胱甘肽的合成 共轭化合物AS的鉴定和定量 二氢呋喃的代谢物及其结合物效应的评价 抗GR和DSU敏感的肿瘤细胞。 长期目标是，根据从这一过程中获得的信息 研究，进行合理的结构修改，寻找更多 强效低毒的抗肿瘤药物，也是为了探索 抑制糖皮质激素受体作为一种新的癌症治疗方法的潜力 以及逆转肿瘤对放射治疗的耐药性和 化疗。

DESCRIPTION: (Principal Investigator's) Diarylsulfonylureas (DSU) have been identified as a new class of antitumor agents. DSU exhibit a broad spectrum of activity against solid tumors and lack the toxicity to proliferating normal tissues, which is often associated with other conventional antitumor agents. Moreover, DSU do not show cross- resistance with other antitumor agents, and are not part of the P- glycoprotein-mediated multidrug resistance (MDR) phenotype, showing great potential in treating tumors which are resistant to current antitumor agents. In spite of numerous efforts, the antitumor mechanism of DSU remains undefined. But it is clear that, unlike other conventional antitumor agents, DSU do not inhibit the synthesis of DNA, RNA or proteins and show no cell cycle dependency suggesting that they act through a potentially unique and novel mechanism. We propose that the antitumor activity of DSU is contributed (or partially contributed) by inhibition of glutathione reductase (GR) in tumor cells by glutathione conjugates-potential metabolites of DSU. GR is an important enzyme to cell viability. Our preliminary results demonstrated that a GR inhibitor related to the glutathione conjugates inhibited DSU-sensitive tumor cell growth 10 times as potent as the parent drug. The proposed research is designed to test this hypothesis and sulofenur, a representative compound of DSU, will be employed to test the hypothesis. The study will involve synthesis of the glutathione conjugates, identification and quantification of the conjugates as metabolites of DSU, as well as evaluation of the conjugates effects against GR and DSU-sensitive tumor cells. The long term objective is, based on the information obtained from this study, to conduct rational structural modification to search for more potent and less toxic antitumor agents, and also to explore the potential of inhibiting GR as a novel approach for cancer therapy, as well as for reversal of tumor resistance to radiation therapy and chemotherapy.