文章：

染色体分离与癌症：揭开谜团

Cancer gene therapy: fringe or cutting edge?

原文发布日期：2001-11-01

DOI: 10.1038/35101008

类型: Review Article

开放获取: 否

要点：

1. Gene therapy is a rational approach to the direct attack of cancer cells based on their molecular defects, but despite encouraging preclinical results and signs of efficacy in early stages of clinical testing, its clinical utility has not been proved.
2. There are three broad approaches to direct cancer gene therapy: expressing tumour-suppressor genes in tumours that lack them (or blocking the expression of activated oncogenes), suicide gene therapy, and selectively replicating viruses.
3. Expression of tumour-suppressor genes in tumour cells causes cell-cycle arrest and/or apoptosis, even though such cells harbour many other genetic changes. Surprisingly, there is also some evidence, at least for expression of TP53, that these effects are not cell autonomous. Clinical trials have revealed that this approach is safe, and there are some signs of efficacy.
4. Blocking the expression of oncogenes, using ribozymes or antisense oligonucleotides, can cause growth arrest or apoptosis in vitro, but its effects are cell autonomous. Pharmacological inhibition of oncoproteins, using small molecules or antibodies, might ultimately prove to be a more viable approach.
5. Suicide gene therapy relies on the expression of an enzyme that converts a harmless prodrug into a potent toxin. Its main advantage is that the toxin can then kill surrounding cells that aren't expressing the vector. Again, suicide gene therapy has proved safe in the clinic but has shown little, if any, therapeutic benefit. Second-generation vectors might address this lack of efficacy.
6. Selectively replicating viruses rely on a property of the tumour cell (such as loss of tumour-suppressor function) that make tumour cells uniquely susceptible to productive infection with the virus. Clinical trials have revealed that the approach is safe, and there are some signs of efficacy.
7. In all these approaches, lack of bioavailability and attack of the viral vectors by the B-cell arm of the immune system are significant problems. Several approaches are being developed to solve these problems, but none have yet been tested in the clinic.

要点翻译：

1. 基因治疗是一种基于癌细胞分子缺陷直接攻击癌细胞的合理策略，但尽管临床前结果令人鼓舞且在临床试验初期显示出有效性迹象，其临床实用性尚未得到证实。
2. 癌症基因治疗主要有三大方向：在缺乏肿瘤抑制基因的肿瘤中表达该类基因（或阻断活化癌基因的表达）、自杀基因治疗，以及选择性复制病毒疗法。
3. 在肿瘤细胞中表达肿瘤抑制基因可引发细胞周期停滞和/或细胞凋亡，即使这些细胞存在诸多其他遗传变异。令人惊讶的是，至少有TP53基因表达证据表明这些效应并非细胞自主性。临床试验证实该方法安全性良好，且存在一定有效性迹象。
4. 通过核酶或反义寡核苷酸阻断癌基因表达可在体外导致生长停滞或细胞凋亡，但该效应具有细胞自主性。使用小分子或抗体对癌蛋白进行药理抑制，最终可能被证明是更可行的策略。
5. 自杀基因治疗依赖于能将无害前体药物转化为强效毒素的酶表达。其主要优势在于毒素可杀死未表达载体的周围细胞。该疗法在临床上已被证实安全性良好，但治疗获益微乎其微。第二代载体或可解决此疗效不足的问题。
6. 选择性复制病毒疗法利用肿瘤细胞特性（如肿瘤抑制功能缺失），使肿瘤细胞独特性易受病毒增殖性感染。临床试验显示该方法安全性良好，并存在一定有效性迹象。
7. 所有这些方法都面临生物利用度不足以及病毒载体被免疫系统B细胞分支攻击的重大挑战。目前正在开发多种解决方案，但尚未进入临床验证阶段。

英文摘要：

Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally — a challenge that has been successfully addressed.

摘要翻译： 

利用基因疗法直接靶向癌细胞，有望根据癌症的分子特征进行治疗。尽管实验室结果令人极其鼓舞，但在基因疗法实现临床目标之前，仍有许多实际障碍需要克服。这些问题虽非无足轻重，但相较于选择性和合理性杀灭癌症这一已成功应对的挑战而言，似乎不再那么难以逾越。

原文链接：

Cancer gene therapy: fringe or cutting edge?