REGULATION OF MULTIDRUG RESISTANCE GENE EXPRESSION

化疗已被广泛而成功地用于治疗。 不同类型的癌症。不幸的是，许多形式的癌症 仍然对化疗无效，以及其他最初有效的 有利的是，以后会产生抗药性。抗药性的出现 在癌症化疗中遇到的一个主要障碍是成功 人类恶性肿瘤的临床治疗的最新进展，至今仍是 重要的未解决的问题。这项研究的主要目的是 阐明多药耐药基因表达的调控机制 在人类恶性肿瘤的发展过程中。 人类癌症中多药耐药的发生与 多药耐药(MDR1)基因的过度表达，它编码一种 质膜能量依赖性外排泵，称为P-糖蛋白(或 多药转运体)，这使得对多药交叉耐药 疏水性天然产物细胞毒药物。的表达 多药耐药基因在人类肿瘤中偶尔出现 在没有明显选择压力的情况下。我们最近展示了 人多药耐药基因启动子是c-Ha-Ras-1癌基因的靶点 和p53抑癌基因，这两个基因与肿瘤有关 进步。C-Ha-RAS-1的刺激作用不是特异性的 单独的mdr1启动子，而突变型p53特异性地刺激 Mdr1启动子和野生型p53具有特异性抑制作用。 目前的研究建议试图：(1)检查以下因素的影响 其他癌基因和抑癌基因，如c-fos、c-jun、c-myc、 和视网膜母细胞瘤基因产物Rb对启动子活性的影响 Mdr1基因；(2)检测和鉴定顺式和反式作用 RAS、P53和Ras对mdr1启动子调控的元件 Rb；(3)建立mdr1基因表达与肿瘤转移的相关性。 肿瘤进展，通过开发组织培养模型系统来研究 稳定转移RAS后mdr1基因在体内的表达 野生型或突变型P53和Rb基因；(4)确定细胞类型- P53和P53对mdr1基因启动子的特异性表达和激活 Rb，以及它们的激活机制。这些结果可能会 肿瘤过程中多药耐药基因激活的重要意义 进展与RAS、P53和Rb基因改变相关。 从这些研究中学到的信息可以用来设计 更合理的化疗方法。

Chemotherapy has been widely and successfully employed for the treatment of various types of cancer. Unfortunately, many forms of cancer are still refractory to chemotherapy, and others that initially respond favorably later become drug resistant. The emergence of drug resistance encountered in cancer chemotherapy poses a major obstacle to the success of clinical treatment of human malignancies, and remains one of the important unsolved problems. The primary objective of this research is to elucidate the mechanisms by which MDR1 gene expression is regulated during the progression of human malignancies. The genesis of multidrug resistance in human cancer is associated with overexpression of the multidrug resistance (MDR1) gene, which encodes a plasma membrane energy-dependent efflux pump termed, P-glycoprotein (or multidrug transporter), which confers cross-resistance to multiple hydrophobic natural product cytotoxic drugs. Expression of the multidrug-resistance gene occasionally occurs de novo in human cancers in the absence of obvious selective pressure. We have recently shown that the human MDR1 gene promoter is a target for the c-Ha-RAS-1 oncogene and the p53 tumor suppressor gene, two genes associated with tumor progression. the stimulatory effect of c-Ha-RAS-1 was not specific for the MDR1 promoter alone, whereas a mutant p53 specifically stimulated the MDR1 promoter and wild-type p53 exerted specific repression. The current research proposal attempts to: (1) examine the effects of other oncogenes and tumor suppressor gene, such as c-fos, c-jun, c-myc, and the retinoblastoma gene product, Rb, on the promoter activity of the MDR1 gene; (2) determine and characterize the cis- and trans-acting elements involved in the modulation of the MDR1 promoter by RAS, p53 and Rb; (3) establish a correlation between the expression of MDR1 gene and tumor progression, by developing a tissue culture model system to study the in vivo expression of MDR1 gene after stable transfer of RAS, or either wild-type or mutant p53 and Rb genes; (4) determine the cell type- specific expression and activation of the MDR1 gene promoter by p53 and Rb, an their mechanisms of activation. These results could have significant implications on the activation of the MDR1 gene during tumor progression associated with genetic alterations in RAS, p53 and Rb. Information learned from these studies could then be utilized to design more rational approaches to chemotherapy.