文章：

提高基于抗体的癌症治疗的疗效

Improving the efficacy of antibody-based cancer therapies

原文发布日期：2001-11-01

DOI: 10.1038/35101072

类型: Review Article

开放获取: 否

要点：

1. Cyclin-dependent kinases (CDKs) are the master regulators of mitosis.They delegate portions of the mitotic programme to other downstream transducers that act directly on various components of mitotic chromosomes, the spindle apparatus and the cytoskeleton.
2. The anaphase-promoting complex/cyclosome (APC/C) normally becomes active at the metaphase–anaphase transition. It triggers the degradation of an anaphase-inhibiting protein, called securin, and cyclin B. Inhibition of the APC/C is one of the principal consequences of spindle-checkpoint activation.
3. In human cells, the formation of a securin–separin complex primes the separin protease for eventual activation in anaphase. Otherwise, securin functions primarily as an inhibitor of the separin protease, which cleaves cohesin bridges, allowing the sister chromatids to move poleward along the mitotic spindle.
4. Genetic instability is a hallmark of virtually all solid tumours. Most cancers are aneuploid and often exhibit cytological abnormalities during mitosis, including abnormal centrosomes, multipolar spindles and lagging chromosomes.
5. More than 100 genes can cause chromosomal instability (CIN) when mutated in yeast cells, many of which have several homologues in humans. These include genes that are involved in chromosome metabolism, spindle assembly and dynamics, cell-cycle regulation and mitotic checkpoint control.
6. Genetic alterations in the mitotic-spindle checkpoint of human cells lead directly to CIN. However, the underlying chromosomal segregration defects can be quite distinct.
7. Cancer cells have numerous defects in their genetic stability mechanisms. The effect of such defects might render most cancers vulnerable to genotoxic challenges that threaten genomic integrity, indicating a possible route to drug discovery.

要点翻译：

1. 细胞周期蛋白依赖性激酶（CDKs）是有丝分裂的核心调控因子。它们将部分有丝分裂程序分配给其他下游转导因子，这些因子直接作用于有丝分裂染色体的各个组分、纺锤体装置和细胞骨架。
2. 后期促进复合物/循环体（APC/C）通常在中期-后期转换阶段被激活。它触发一种称为安全蛋白的后期抑制蛋白以及细胞周期蛋白B的降解。APC/C的抑制是纺锤体检查点激活的主要后果之一。
3. 在人类细胞中，安全蛋白-分离蛋白复合物的形成促使分离蛋白酶在后期最终激活。否则，安全蛋白主要作为分离蛋白酶的抑制剂发挥作用，该酶可切割粘连蛋白桥，使姐妹染色单体能够沿有丝分裂纺锤体向极移动。
4. 遗传不稳定性是几乎所有实体肿瘤的标志。大多数癌症存在非整倍体，且在有丝分裂过程中常表现出细胞学异常，包括异常中心体、多极纺锤体和滞后染色体。
5. 在酵母细胞中突变时，超过100个基因可导致染色体不稳定性（CIN），其中许多基因在人类中存在多个同源物。这些基因涉及染色体代谢、纺锤体组装与动力学、细胞周期调控以及有丝分裂检查点控制。
6. 人类细胞有丝分裂纺锤体检查点的遗传改变直接导致CIN。然而，潜在的染色体分离缺陷可能截然不同。
7. 癌细胞的遗传稳定性机制存在众多缺陷。这些缺陷的影响可能使大多数癌症在面对威胁基因组完整性的基因毒性挑战时显得脆弱，这为药物研发指明了潜在路径。

英文摘要：

At the doses used clinically, chemotherapy is believed to kill melanoma by a final common 'mitochondrial' pathway that leads to apoptosis. Similarly, several natural defence mechanisms kill melanoma by the same pathways. A corollary to the latter is that survival of melanoma in the host is due to the development of anti-apoptotic mechanisms in melanoma cells. What are these mechanisms? And how might we bypass them to improve the treatment of melanoma?

摘要翻译： 

在临床使用剂量下，化疗药物被认为通过最终共同的"线粒体"通路导致黑色素瘤细胞凋亡而将其杀灭。同样，多种天然防御机制也通过相同途径清除黑色素瘤。由此可推论：黑色素瘤在宿主体内存活的原因在于瘤细胞形成了抗凋亡机制。这些机制具体是什么？我们该如何绕过这些机制以提升黑色素瘤的治疗效果？

原文链接：

Improving the efficacy of antibody-based cancer therapies