Reed C J
The Burnham Institute, La Jolla, CA 92037, USA.
Semin Hematol. 2000 Oct;37(4 Suppl 7):9-16. doi: 10.1016/s0037-1963(00)90055-6.
Virtually all human cells are endowed with the capacity to commit suicide using an evolutionarily conserved mechanism that involves activation of caspase-family cell death proteases. Caspase activation culminates in a cell death process known as "apoptosis." The activation of these intracellular proteases is carefully controlled through a delicate balance of anti- and pro-death proteins, serving to precisely regulate cell life span. Defects in the natural death pathway promote tumorigenesis by prolonging cell life span and hence cell accumulation. Low-grade B-cell malignancies, particularly follicular lymphoma and chronic lymphocytic leukemia (CLL) represent quintessential examples of human neoplasms characterized primarily by a problem with cell death rather than cell cycle. Because the cell suicide pathway is also required for tumor eradication by the immune system, anticancer drugs, and irradiation, cancer-associated defects in the cellular apoptosis machinery also play an important role in treatment failures. Monoclonal antibody-based therapies may provide opportunities to either bypass defects in apoptosis pathways or to activate latent apoptotic programs in cancer cells, particularly in lymphoid malignancies where tissue-specific antigens can be exploited for cell-selective activation of apoptosis. Recent knowledge about apoptosis pathways is reviewed, and some examples of opportunities for therapeutic intervention are discussed.
实际上，所有人类细胞都具备利用一种进化上保守的机制进行自我毁灭的能力，该机制涉及半胱天冬酶家族细胞死亡蛋白酶的激活。半胱天冬酶的激活最终导致一种被称为“凋亡”的细胞死亡过程。这些细胞内蛋白酶的激活通过抗死亡蛋白和促死亡蛋白之间的微妙平衡受到严格控制，从而精确调节细胞寿命。自然死亡途径中的缺陷通过延长细胞寿命进而促进细胞积累，从而引发肿瘤发生。低度B细胞恶性肿瘤，尤其是滤泡性淋巴瘤和慢性淋巴细胞白血病（CLL），是人类肿瘤的典型例子，其主要特征是细胞死亡而非细胞周期出现问题。由于细胞自杀途径也是免疫系统、抗癌药物和辐射根除肿瘤所必需的，细胞凋亡机制中与癌症相关的缺陷在治疗失败中也起着重要作用。基于单克隆抗体的疗法可能提供机会，要么绕过凋亡途径中的缺陷，要么激活癌细胞中潜在的凋亡程序，特别是在淋巴恶性肿瘤中，其中组织特异性抗原可用于细胞选择性激活凋亡。本文综述了关于凋亡途径的最新知识，并讨论了一些治疗干预机会的实例。
