The Spindle Checkpoint as a Target for Cancer

描述：（申请人提供） 纺锤体检查点是一种信号传导途径，通常促进 染色体在M期的适当分离。如果在有丝分裂中染色体 没有在有丝分裂纺锤体上正确对齐，纺锤体检查点停止 细胞周期进程之前中期到后期的过渡。这 延迟使染色体有更多的时间附着在纺锤体上 微管并移动到细胞中平面的适当位置。 可以人为地强制单个细胞覆盖纺锤体检查点 通过注射针对纺锤体检查点的蛋白质的抗体或通过 转染编码突变体、显性阴性纺锤体检查点的cDNA proteins.这些干预会导致染色体的大量不平衡， 可以直接致死或引起细胞凋亡的分离。肿瘤细胞通常 与正常体细胞相比，表现出有缺陷的检查点反应。的 肿瘤细胞诱导细胞周期检查点的反应相对较弱 可能是抗癌疗法显示出一些 对肿瘤的选择性。专门针对细胞周期检查点的药物 可用于进一步使肿瘤细胞群对治疗敏感。那里 目前还没有细胞渗透性药物可以抑制纺锤体 检查站这里提出的项目是开发和建立一个高 通过筛选可以穿透细胞膜和细胞外基质的药物 纺锤体检查点纺锤体的几种蛋白质成分 检查点通路没有其他功能。因此， 可以发现该途径的特定小分子抑制剂。 有效的药物已经确定，纺锤体的特定蛋白质 将确定靶向的检查点途径。预计 这些药物将在临床上用于抗癌治疗， 特别是当与化疗性抗微管药物联合使用时 诸如长春花生物碱和紫杉烷类的药物， 纺锤体检查点的诱导物。

DESCRIPTION: (provided by applicant) The spindle checkpoint is a signaling pathway that normally promotes the proper segregation of chromosomes in M phase. If in mitosis the chromosomes are not properly aligned on the mitotic spindle, the spindle checkpoint halts cell cycle progression prior to the metaphase-to-anaphase transition. This delay allows more time for chromosomes to attach the mtitotic spindle microtubules and move to their proper positions at the midplane of the cell. Individual cells can be artificially forced to override the spindle checkpoint by the injection of antibodies to proteins of the spindle checkpoint or by transfection of cDNA's encoding mutant, dominant-negative spindle checkpoint proteins. These interventions induce massive imbalances in chromosome segregation that can be directly lethal or cause apoptosis. Tumor cells often exhibit defective checkpoint responses compared to normal somatic cells. The relative weakness of tumor cells to induce cell cycle checkpoints in response to damage may be one mechanism by which anti-cancer therapies show some selectivity for tumors. Drugs that specifically target cell cycle checkpoints may be useful in further sensitizing tumor cell population to therapy. There are currently no cell permeable drugs that can inactivate the spindle checkpoint. The project proposed here is to develop and institute a high throughput screen for drugs that can penetrate cell membranes and inactivate the spindle checkpoint. Several of the protein components of the spindle checkpoint pathway have no other functions. Thus it is reasonable that specific small molecule inhibitors of this pathway can be found. Once effective drugs have been identified, the specific proteins of the spindle checkpoint pathway that are targeted will be determined. It is anticipated that these drugs will be clinically useful for anti-cancer therapy, particularly when used in combination with chemotherapeutic anti-microtubule drugs such as the vinca alkaloids and the taxanes which are themselves potent inducers of the spindle checkpoint.