CELL CYCLE REGULATION AND CHEMOSENSITIVITY

细胞周期调节和化学敏感性

• 批准号: 6160999
• 负责人: P M O'CONNOR
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160999
• 关键词: DNA damage; DNA repair; antineoplastics; apoptosis; cell cycle; cell cycle proteins; chemosensitizing agent; drug screening /evaluation; enzyme activity; gene mutation; molecular cloning; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplastic cell; protein kinase; protein structure function; tumor suppressor genes

Our research group is utilizing enabling technologies to exploit emerging knowledge of molecular events that participate in the evolution of cancer to both decipher the molecular basis of chemosensitivity and to discover new and more selective chemotherapeutic agents. Current emphasis is placed on the (1) development of isogenic model systems derived from normal human cells to study the biological and pharmacological impact of genes commonly altered in human cancer and (2) investigation of control elements in cell cycle pathways for anticancer drug discovery. Our current research portfolio was shaped, in part, by our studies on the role of the p53 tumor suppressor in chemosensitivity (OConnor et al., Cancer Res., 53: 4776, 1993; Fan et al., Cancer Res., 54:5824, 1994; Fan et al., Cancer Res., 55:1649, 1995; Fan et al., Oncogene, 14: 2127, 1997). These studies have recently been extended to the 60 cell lines of the NCI anticancer drug screen (OConnor et al., Cancer Res., 57:4285, 1997; Weinstein et al., Science, 275:343, 1997) and agents identified in this assay that might exploit defective-p53 function for their activity are presently being analyzed. We are now focused on the generation of in vitro model systems based on normal human mammary epithelial cells and derivatives lacking p53 function due to a retrovirally-delivered dominant-negative mutant p53 transgene. These studies act as a starting point to assess the influence of other common genetic alterations seen in human breast cancer on the biology and pharmacology of normal cells. We have also found that drugs, such as pentoxifylline and UCN-01, preferentially abrogated the G2 checkpoint in p53-defective cancer cells (Fan et al., Cancer Research, 55:1649, 1995: Wang et al., JNCI, 88:956, 1996). We have found that UCN-01 abrogates G2 arrest through a Cdc2-dependent pathway by relieving Cdc2- inhibitory phosphorylations. We have excluded the Wee1 kinase as a direct target of UCN-01 action. Current investigations include a structure-activity relationship study of the UCN-01 molecule coupled with in vitro assessment of other targets of the G2/M regulatory machinery. Enabling technologies being used include retroviral gene delivery, microgridded cDNA arrays, multiwell-based drug analysis tools and high-throughput biochemical analysis.

我们的研究小组正在利用使能技术来开发 参与进化的分子事件的新兴知识 癌症的分子基础和化学敏感性 发现新的、更具选择性的化疗药物。当前的 重点是（1）等基因模型系统的开发 从正常人体细胞中提取来研究生物和 人类癌症中常见改变的基因的药理学影响和 (2) 抗癌细胞周期途径控制元件的研究 药物发现。我们当前的研究组合在一定程度上是由 我们关于 p53 肿瘤抑制因子在化疗敏感性中的作用的研究 (OConnor 等人，癌症研究，53：4776，1993；Fan 等人，癌症研究， 54:5824, 1994; Fan 等人，《癌症研究》，55：1649，1995；范等人， 癌基因，14：2127，1997）。这些研究最近已扩展到 NCI 抗癌药物筛选的 60 个细胞系（OConnor 等人， 癌症研究，57：4285，1997； Weinstein 等人，《科学》，275：343，1997） 以及在该测定中发现的可能利用缺陷-p53 的试剂 目前正在分析其活动的功能。我们现在 专注于基于正常的体外模型系统的生成 人类乳腺上皮细胞及其衍生物缺乏 p53 功能 逆转录病毒传递的显性失活突变体 p53 转基因。 这些研究作为评估其他因素影响的起点 人类乳腺癌中常见的生物学基因改变 和正常细胞的药理学。我们还发现，药物，例如 如己酮可可碱和 UCN-01，优先废除 G2 检查点 在 p53 缺陷型癌细胞中（Fan 等人，Cancer Research，55：1649， 1995 年：Wang 等人，JNCI，88：956，1996）。我们发现UCN-01 通过缓解 Cdc2- 依赖的 Cdc2 途径消除 G2 停滞 抑制性磷酸化。我们已排除 Wee1 激酶作为 UCN-01行动的直接目标。目前的调查包括 UCN-01分子偶联的构效关系研究 对 G2/M 监管的其他目标进行体外评估 机械。正在使用的使能技术包括逆转录病毒基因 递送、微网格 cDNA 阵列、基于多孔的药物分析工具 和高通量生化分析。