Sugimoto Y
Division of Experimental Chemotherapy, Japanese Foundation for Cancer Research.
Gan To Kagaku Ryoho. 1999 Jan;26(1):1-9.
Myelosuppression is a major dose-limiting factor in cancer chemotherapy. Introduction of drug-resistance genes into bone marrow cells of cancer patients has been proposed to overcome this limitation. In theory, any gene whose expression protects cells against the toxic effects of chemotherapy should be useful in vivo for this purpose. Among such genes, human multidrug-resistance gene (MDR1) and O6-methylguanine DNA methyltransferase gene (MGMT) have been studied most extensively for this purpose, and clinical trials of drug-resistance gene therapy have been started in the US for cancer patients who undergo high-dose chemotherapy with autologous hematopoietic stem cell transplantation. In Japan, our clinical protocol of MDR1 gene therapy, "A clinical study of drug-resistance gene therapy to improve the efficacy and safety of chemotherapy against breast cancer", has been approved by our IRB and submitted to the government. To improve the efficacy and safety of this drug-resistance gene therapy, we have constructed a series of MDR1-bicistronic retrovirus vectors using a retrovirus backbone of Harvey murine sarcoma virus and internal ribosome entry site (IRES) from picornavirus to coexpress a second gene with the MDR1 gene. MDR1-MGMT bicistronic vectors can be used to protect bone marrow cells of cancer patients from combination chemotherapy with MDR1-related anticancer agents and nitrosoureas. In addition, MDR1-bicistronic retrovirus vectors can be designed to use the MDR1 gene as an in vivo selectable marker to enrich the transduced cells which express therapeutic genes, if disease is curable by the expression of a single-peptide gene in bone marrow cells or any types of peripheral blood cells.
骨髓抑制是癌症化疗中的主要剂量限制因素。有人提出将耐药基因导入癌症患者的骨髓细胞以克服这一限制。理论上，任何其表达能保护细胞免受化疗毒性作用的基因在体内都应为此目的有用。在这类基因中，人类多药耐药基因（MDR1）和O6-甲基鸟嘌呤DNA甲基转移酶基因（MGMT）为此目的研究得最为广泛，在美国，针对接受高剂量化疗并进行自体造血干细胞移植的癌症患者已启动了耐药基因治疗的临床试验。在日本，我们的MDR1基因治疗临床方案“提高乳腺癌化疗疗效和安全性的耐药基因治疗临床研究”已获机构审查委员会批准并提交给政府。为提高这种耐药基因治疗的疗效和安全性，我们使用哈维鼠肉瘤病毒的逆转录病毒骨架和微小核糖核酸病毒的内部核糖体进入位点（IRES）构建了一系列MDR1双顺反子逆转录病毒载体，以便与MDR1基因共表达第二个基因。MDR1-MGMT双顺反子载体可用于保护癌症患者的骨髓细胞免受与MDR1相关的抗癌药物和亚硝基脲联合化疗的影响。此外，如果疾病可通过骨髓细胞或任何类型外周血细胞中单一肽基因的表达治愈，MDR1双顺反子逆转录病毒载体可设计为将MDR1基因用作体内选择标记，以富集表达治疗性基因的转导细胞。
