文章：

结直肠癌基因治疗的临床进展

Clinical development of gene therapy for colorectal cancer

原文发布日期：2003-08-01

DOI: 10.1038/nrc1147

类型: Review Article

开放获取: 否

要点：

1. Colorectal cancer (CRC) is the second most common type of cancer in the Western world. Despite improvements in treatment, CRC recurs in up to 50% of patients and ultimately proves to be fatal.
2. CRC lends itself to various gene-therapy approaches, which include gene correction, virus-directed enzyme–prodrug therapy, immunogenetic manipulation and virotherapy.
3. CRC can be confined to organs (liver) or compartments (peritoneal cavity) for most of its natural history, allowing regional administration of the gene vector.
4. Gene-replacement trials have been initiated combining adenoviral TP53, which can act as a cytotoxic sensitizer, and conventional chemotherapy.
5. Virus-directed enzyme–prodrug therapy involves viral delivery of a transgene encoding an enzyme that can convert a non-toxic prodrug to a cytotoxic species. Early-phase clinical trials have been initiated with cytosine deaminase/fluorocytosine, herpes simplex virus thymidine kinase/gancyclovir and nitroimidazole reductase/CB1954.
6. Adenoviral transduction of allogeneic CRC cells with the gene encoding interleukin-2, vaccinia and fowl-pox vaccines aimed at inducing T-cell responses to carcinoembryonic antigen, and manipulation of MHC expression have all produced clinical immune responses in trials of immunogenetic therapies.
7. Virotherapy, with replication-competent adenoviruses engineered to proliferate in CRC cells with mutant p53 or RB, has been used to treat patients with hepatic metastases, in combination with 5-fluorouracil.
8. Randomized clinical trials are required to show the added value of gene therapy in the management of CRC; it is probable that combination gene therapy will be required to complement conventional chemotherapy.

要点翻译：

1. 结直肠癌（CRC）是西方世界第二常见的癌症类型。尽管治疗手段有所改进，但仍有高达50%的患者出现复发并最终致命。
2. 结直肠癌适用于多种基因治疗方法，包括基因校正、病毒导向酶前体药物疗法、免疫基因操作和病毒疗法。
3. 在其自然史的大部分阶段，结直肠癌可局限于器官（肝脏）或腔室（腹膜腔），这使得基因载体能够进行局部给药。
4. 基因替换试验已启动，将腺病毒TP53（可作为细胞毒性增敏剂）与常规化疗相结合。
5. 病毒导向酶前体药物疗法涉及通过病毒递送编码酶的转基因，该酶能将无毒的前体药物转化为细胞毒性物质。已启动早期临床试验，涉及胞嘧啶脱氨酶/氟胞嘧啶、单纯疱疹病毒胸苷激酶/更昔洛韦和硝基咪唑还原酶/CB1954。
6. 在免疫基因疗法试验中，采用编码白细胞介素-2的基因对同种异体结直肠癌细胞进行腺病毒转导、旨在诱导T细胞对癌胚抗原产生反应的痘苗病毒和鸡痘疫苗，以及MHC表达的操作，均产生了临床免疫反应。
7. 病毒疗法采用复制型腺病毒（经改造可在p53或RB突变的结直肠癌细胞中增殖），已与5-氟尿嘧啶联合用于治疗肝转移患者。
8. 需要进行随机临床试验来证明基因治疗在结直肠癌管理中的附加价值；很可能需要联合基因治疗来补充常规化疗。

英文摘要：

Colorectal cancer (CRC) is the second most common type of malignancy in Western nations. Improvements in surgical and radiotherapeutic techniques and the increased availability of new cytotoxic drugs have improved outcome, but 50% of patients still die from recurrent or metastatic disease. Several features of its natural history render CRC a good candidate for gene therapy. Techniques include gene replacement, virus-directed enzyme–prodrug therapy, immune manipulation and virotherapy, all of which have entered clinical trials.

摘要翻译： 

结直肠癌（CRC）是西方国家第二常见的恶性肿瘤。尽管手术和放疗技术不断改进，新型细胞毒性药物日益增多，患者预后仍仅小幅提升，50%的患者最终死于复发或转移性疾病。其自然病史中的若干特点使CRC成为基因治疗的良好候选。相关技术包括基因替代、病毒导向的酶-前药疗法、免疫调控和病毒疗法，均已进入临床试验阶段。

原文链接：

Clinical development of gene therapy for colorectal cancer