文章：

保护造血细胞免受细胞毒性癌症药物侵害的基因疗法

Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs

原文发布日期：2002-06-01

DOI: 10.1038/nrc823

类型: Review Article

开放获取: 否

要点：

1. Chemotherapeutic drugs are most toxic to rapidly proliferating cells in the gastrointestinal tract and the blood-forming haematopoietic system. As a result, the dosage of the chemotherapeutic agents must be reduced, along with the likelihood of tumour eradication.
2. Gene therapy approaches have been developed to promote stable integration of drug-resistance genes in pluripotent haematopoietic stem cells.
3. Protecting a cancer patient's haematopoietic stem cells from the toxic effects of cancer therapies involves autologous transplantation of genetically modified bone-marrow cells. These cells are transduced ex vivo with a retroviral vector that contains a drug-resistance gene before being transplanted back into the patient.
4. The choice of envelope protein expressed by the viral vector has proven to be an important determinant of stem-cell transduction efficiency, due to the fact that the receptors for viral envelopes are expressed at varying levels on the stem-cell surface.
5. Mouse oncoretroviruses can only gain access to nuclear chromatin during mitosis, whereas lentiviral vectors can enter an intact nucleus directly through the nuclear pores.
6. Various drug-resistance genes have been shown to protect haematopoietic stem cells in animal models. These include the multidrug resistance 1 gene (Mdr1), dihydrofolate reductase (Dhfr) and methylguanine methyltransferase (Mgmt).
7. Several clinical trials have evaluated the feasiblity of haematopoietic protection using MDR1-expressing vectors in adult cancer patients.
8. Haematopoietic stem-cell gene therapy offers an opportunity to widen the anticancer therapeutic index.

要点翻译：

1. 化疗药物对胃肠道和造血系统中快速增殖的细胞具有最强毒性作用，因此必须降低化疗药物剂量，但这同时会降低肿瘤根除的可能性。
2. 基因治疗方法已被开发用于促进耐药基因在多能造血干细胞中的稳定整合。
3. 通过自体移植经基因修饰的骨髓细胞，可保护癌症患者的造血干细胞免受癌症治疗的毒性影响。这些细胞在体外通过含耐药基因的逆转录病毒载体转导后，再回植患者体内。
4. 病毒载体表达的外膜蛋白选择被证明是决定干细胞转导效率的关键因素，因为病毒外膜受体的表达水平在干细胞表面存在差异。
5. 小鼠致癌逆转录病毒仅能在有丝分裂期间进入核染色质，而慢病毒载体可直接通过核孔进入完整细胞核。
6. 动物模型研究证实多种耐药基因可保护造血干细胞，包括多药耐药基因1（Mdr1）、二氢叶酸还原酶基因（Dhfr）和甲基鸟嘌呤甲基转移酶基因（Mgmt）。
7. 多项临床试验已评估在成人癌症患者中使用表达MDR1载体实现造血保护的可行性。
8. 造血干细胞基因治疗为拓宽抗癌治疗窗提供了新途径。

英文摘要：

One of the most important complications of cancer chemotherapy is the toxic effect that the drugs have on normal tissues — particularly the bone marrow. Several gene-therapy vectors have been developed with the aim of expressing drug-resistance genes specifically in bone-marrow stem cells, so protecting them from chemotherapeutics. The feasibility of this approach has been established in animal model systems, and recent advances in the design of gene-therapy vectors offer promise for future clinical applications.

摘要翻译： 

癌症化疗最重要的并发症之一是药物对正常组织——尤其是骨髓——的毒性作用。研究者已开发出多种基因治疗载体，旨在仅在骨髓干细胞中表达耐药基因，从而保护它们免受化疗药物的损伤。该方法的可行性已在动物模型系统中得到证实，而基因治疗载体设计的最新进展为未来临床应用带来了希望。

原文链接：

Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs