MULTIDRUG RESISTANCE GENES--ANALYSIS AND APPLICATIONS

化疗药物耐药性的发展， 恶性细胞在成功的癌症治疗中仍然是一个重要的问题 疗法 在体外分析的机制，同时 对多种化疗药物具有耐药性， 与基因组特定区域的扩增相关。 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 区域和多药耐药细胞中过表达的基因 线 来自该扩增区域的分子探针将用于 推进我们对化疗方案的理解， 未来 多药耐药基因的实际应用 转基因造血干细胞将扩大我们的 造血的知识，并代表了第一步， 利用对化疗药物有抗性的造血干细胞 作为化疗方案组成部分的药物 和骨髓移植。 这些研究的具体目标是：1）表征 负责多药耐药基因的cDNA克隆 抗性，2）表征由所述抗性基因编码的蛋白质， 导致多药耐药的cDNA克隆，3） 多药扩增机制的表征 耐药基因，4）评估正在接受急性 淋巴细胞白血病的发展扩增 多药耐药基因及其与 化疗失败，5）体内模型的开发， 多药耐药发展的直接分析 分子水平，6）逆转录病毒载体的构建 含有负责多药耐药性的基因，以及7） 体内选择造血干细胞， 多药耐药基因开发模型系统， 造血功能分析和骨髓保护 化疗剂。

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.