GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

多重耐药基因的遗传分析

• 批准号: 3752752
• 负责人: M DEAN
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752752
• 关键词: Escherichia coli; P glycoprotein; adenosine triphosphate; chromosomes; computer assisted sequence analysis; cytogenetics; fluorescent dye /probe; gene expression; genetic mapping; human genetic material tag; in situ hybridization; membrane transport proteins; molecular cloning; multidrug resistance; nucleic acid sequence; pharmacogenetics; sequence tagged sites

The development of resistance to drugs is a major limitation to the successful treatment of malignancies with chemotherapy. Multidrug resistance (MDR), defined as tumors that are resistant to more than one drug, is particularly problematic. MDR is partially due to the overexpression of the P-glycoprotein/MDR genes. These genes function as adenosine triphosphate (ATP)-dependent transporters that can extrude a large variety of hydrophobic compounds from the cell. The normal function of the human MDR genes is unknown; however, they are part of a super-family of membrane-bound transport molecules, the ATP-binding cassette (ABC) superfamily. In Escherichia coli at least 25 ABC genes have been identified, whereas in humans only 8 members of the gene superfamily have been described. Human ABC genes are involved in several diseases such as cystic fibrosis and adrenoleuko-dystrophy. In an effort to characterize new human ABC genes, we have screened the expressed sequence tags database and identified several new sequences that may represent ABC genes. To date four clones, containing sequences of the genes that are members of the ABC superfamily, were identified. The four genes display extensive diversity in sequence and expression pattern. In addition, the new genes, mapped using somatic cell hybrid panels and fluorescence in situ hybridization, are located on chromosomes 1, 9 and 10; at locations distinct from previously mapped genes of this superfamily. Expression studies in different tumors are in progress, the ultimate goal being a functional characterization of the described genes. Furthermore, genetic characterization of the ABC genes may reveal a number of functionally important molecules that may be involved in the transport of substances by cells.

抗药性的发展是限制人类健康的主要因素。 用化疗成功地治疗了恶性肿瘤。多药联用 耐药(MDR)，定义为对一种以上耐药的肿瘤 毒品，尤其成问题。MDR的部分原因是 P-糖蛋白/多药耐药基因过度表达。这些基因的功能是 三磷酸腺苷(ATP)依赖的转运体可以挤出 细胞中含有种类繁多的疏水化合物。正常的 人类多药耐药基因的功能尚不清楚；然而，它们是 膜结合转运分子超家族--ATP结合 卡带(ABC)超家族。在大肠杆菌中至少有25个ABC基因 已经被确认，而在人类中只有8个基因成员 超家族已被描述。人类的ABC基因涉及几个 囊性纤维化和肾上腺皮质营养不良等疾病。在一次努力中 为了鉴定新的人类ABC基因，我们筛选了表达的 序列标签数据库，并确定了几个新的序列，可能 代表ABC基因。到目前为止，有四个克隆，包含 确定了属于ABC超家族成员的基因。四个 基因在序列和表达模式上表现出广泛的多样性。 此外，使用体细胞杂交面板和 荧光原位杂交，位于第1、9和9号染色体上 10；位于与先前定位的这一基因不同的位置 超级大家庭。在不同肿瘤中的表达研究正在进行中， 最终目标是对所描述的基因进行功能表征。 此外，ABC基因的遗传特征可能揭示出 可能涉及的具有重要功能的分子的数量 细胞对物质的运输。