MULTIDRUG RESISTANCE GENES--ANALYSIS AND APPLICATIONS

多重耐药基因--分析与应用

基本信息

批准号：
3079730
负责人：
James M Croop
金额：
$ 8.88万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-07-01 至 1992-06-30
项目状态：
已结题

项目摘要

The development of resistance to chemotherapeutic agents by malignant cells remains a significant problem in successful cancer therapy. In vitro analysis of a mechanism which simultaneously conveys resistance to multiple chemotherapeutic agents has been associated with amplification of a specific region of the genome. The techniques of molecular biology, cell biology and recombinant retroviral vectors will be utilized in characterizing this amplified region and the genes overexpressed in multidrug resistant cell lines. Molecular probes from this amplified region will be used to advance our understanding the chemotherapeutic protocols of the future. The practical application of multidrug resistance genes transduced into hematopoetic stem cells will expand our knowledge of hematopoesis and represents the first step towards utilizing hematopoetic stem cells resistant to chemotherapeutic agents as an integral component of chemotherapeutic regimens and bone marrow transplantation. The specific aims of these studies will be: 1) characterization of the cDNA clones to the gene(s) responsible for multidrug resistance, 2) characterization of the protein(s) encoded by the cDNA clones which are responsible for multidrug resistance, 3) characterization of the mechanism of amplification of multidrug resistance genes, 4) evaluation of children being treated for acute lymphoblastic leukemia for the development of amplification of multidrug resistance gene(s) and its relationship to chemotherapeutic failures, 5) development of in vivo models for the direct analysis of the development of multidrug resistance at the molecular level, 6) construction of a retroviral vector containing the gene responsible for multidrug resistance, and 7) selection in vivo of hematopoetic stem cells carrying the multidrug resistant gene to develop model systems for the analysis of hematopoesis and protection of bone marrow from chemotherapeutic agents.

化疗药物耐药性的发展恶性细胞仍然是成功癌症的一个重要问题治疗。体外分析同时作用的机制对多种化疗药物产生耐药性与基因组特定区域的扩增有关。分子生物学、细胞生物学和重组技术逆转录病毒载体将用于表征这种扩增的多重耐药细胞中过度表达的区域和基因线。来自该扩增区域的分子探针将用于增进我们对化疗方案的理解未来。多药耐药基因的实际应用转入造血干细胞将扩大我们的造血知识，代表着迈向造血的第一步利用对化疗有抵抗力的造血干细胞药物作为化疗方案的一个组成部分和骨髓移植。这些研究的具体目标是：1）表征负责多种药物的基因的 cDNA 克隆抗性，2) 编码蛋白质的表征导致多重耐药性的 cDNA 克隆，3) 多药放大机制的表征耐药基因，4）评估接受急性治疗的儿童淋巴细胞白血病的发展放大多药耐药基因及其与化疗失败，5）开发体内模型直接分析多药耐药性的发展分子水平，6）逆转录病毒载体的构建含有负责多重耐药性的基因，7) 体内选择携带该基因的造血干细胞多重耐药基因开发模型系统造血及骨髓保护分析化疗剂。