The Spindle Checkpoint as a Target for Cancer

描述：(申请人提供) 纺锤体检查点是一条信号通路，通常促进 M期染色体的适当分离。如果在有丝分裂中，染色体 未在有丝分裂纺锤体上正确对齐，纺锤体检查点停止 中期到后期过渡之前的细胞周期进程。这 延迟使染色体有更多的时间连接有丝分裂的纺锤体 微管并移动到它们在细胞中面的适当位置。 可以人为地强制单个细胞覆盖纺锤形检查点 通过注射纺锤体检查点的蛋白抗体或通过 编码突变型显性负纺锤体检查点基因的转染 蛋白质。这些干预措施导致了大量的染色体失衡。 可直接致死或导致细胞凋亡的隔离。肿瘤细胞常常 与正常体细胞相比，表现出有缺陷的检查点反应。这个 相对较弱的肿瘤细胞诱导细胞周期检查点的反应 损伤可能是抗癌治疗显示出一些 对肿瘤的选择性。针对细胞周期检查点的药物 可能有助于进一步提高肿瘤细胞群体对治疗的敏感性。那里 目前还没有能使纺锤体失活的细胞通透性药物 检查站。在这里提出的项目是开发和建立一个高 能够穿透细胞膜并灭活的药物的吞吐量筛查 主轴检查点。纺锤体的几种蛋白质成分 检查点通路没有其他功能。因此，这是合理的 可以找到这一途径的特定小分子抑制剂。一次 已经确定了有效的药物，纺锤体的特定蛋白质 将确定目标检查点路径。这是意料之中的 这些药物将在临床上用于抗癌治疗， 特别是与化疗抗微管联合使用时 长春花碱和紫杉烷等本身有效的药物 主轴检查点的诱导器。

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.