文章：

促进细胞凋亡作为癌症药物发现的策略

Promoting apoptosis as a strategy for cancer drug discovery

原文发布日期：2005-10-20

DOI: 10.1038/nrc1736

类型: Review Article

开放获取: 否

要点：

1. In many cancers, the normal process for eliminating unwanted cells (apoptosis) is deregulated.
2. The deregulation of apoptosis leads to the unchecked growth of tumours and the development of resistance to chemotherapy.
3. Drugs that restore apoptosis might selectively kill cancer cells that have triggered a death signal and have become dependent on the deregulation of apoptosis pathways.
4. Agonistic antibodies against the tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and a soluble, truncated TRAIL ligand are in phase I/II clinical trials for the treatment of cancer.
5. BCL2 antisense oligonucleotides are in phase III clinical trials and pre-registration, and small-molecule BCL2-family inhibitors are in early phase I clinical trials and in late preclinical discovery for the treatment of chronic lymphocytic leukaemia and solid tumours.
6. IAP (inhibitor of apoptosis) protein inhibitors, MDM2 antagonists and other apoptosis-inducing compounds are under preclinical examination for possible use in cancer therapy.
7. For these compounds to succeed, it will be important to test them in well-designed clinical trials to determine the cancer patients that are most likely to respond to the particular agent, the optimum dose and schedule, and the best combination with other drugs.

要点翻译：

1. 在许多癌症中，清除异常细胞的正常过程（细胞凋亡）出现失调。
2. 细胞凋亡失调导致肿瘤不受控制地生长，并对化疗产生耐药性。
3. 恢复细胞凋亡的药物或能选择性杀死已触发死亡信号、且依赖凋亡通路失调的癌细胞。
4. 针对肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体的激动性抗体及可溶性截短型TRAIL配体已进入I/II期临床试验，用于癌症治疗。
5. BCL2反义寡核苷酸进入III期临床试验和预注册阶段，小分子BCL2家族抑制剂处于早期I期临床试验及临床前研究后期，用于治疗慢性淋巴细胞白血病和实体瘤。
6. IAP（凋亡抑制蛋白）抑制剂、MDM2拮抗剂及其他凋亡诱导化合物正处于临床前研究阶段，可能用于癌症治疗。
7. 这些药物要取得成功，关键在于通过精心设计的临床试验确定最可能对特定药物产生应答的癌症患者类型、最佳剂量与用药方案，以及与其他药物联合使用的最佳策略。

英文摘要：

Apoptosis is deregulated in many cancers, making it difficult to kill tumours. Drugs that restore the normal apoptotic pathways have the potential for effectively treating cancers that depend on aberrations of the apoptotic pathway to stay alive. Apoptosis targets that are currently being explored for cancer drug discovery include the tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, the BCL2 family of anti-apoptotic proteins, inhibitor of apoptosis (IAP) proteins and MDM2.

摘要翻译： 

在许多癌症中，细胞凋亡失调，使得肿瘤难以被清除。能够恢复正常凋亡通路的药物，有望有效治疗那些依赖凋亡通路异常而存活的癌症。目前，用于癌症药物研发的凋亡靶点包括：肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体、抗凋亡蛋白BCL2家族、凋亡抑制蛋白（IAP）以及MDM2。

原文链接：

Promoting apoptosis as a strategy for cancer drug discovery