TUBULIN GENES AND DRUG RESISTANCE

描述：(摘自调查员S摘要)鉴于紫杉烷和 长春花碱是mdr1基因产物P-糖蛋白的底物。 (Pgp)，并考虑到Pgp并不是在所有临床肿瘤标本中都表达， 研究人员推测，对这些病毒产生抵抗的其他机制 可以表示药物的类别。微管蛋白是紫杉烷的靶标。 和长春花碱。因此，修订后的申请的目标是 探索对这些药物的其他耐药机制，重点是 微管蛋白基因。为了支持这一想法，一些细胞系被选为 对紫杉醇的抗性表达了改变的β-微管蛋白。调查员 因此假设微管蛋白亚型表达的变化， 尤其是相对丰度的变化，是造成这种形式的 阻力，并提出了4个具体目标来检验这一假设：(1) 测定微管蛋白亚型在非多药耐药模型中的表达 白血病、乳腺癌和卵巢癌中的微管蛋白靶向细胞毒素； 微管蛋白基因表达改变对药物敏感性和细胞毒副反应的影响 转基因细胞微管组装动力学；(3)药物调控 通过下调特定微管蛋白基因的表达来提高敏感性 反义构建物和寡核苷酸；(4)研究微管蛋白亚型 患者手术前后肿瘤标本中的表达 用紫杉烷或长春花碱治疗。

DESCRIPTION: (taken from investigator s abstract) Given that taxanes and vinca alkaloids are substrates for the mdr1 gene product, P-glycoprotein (Pgp), and given that Pgp is not expressed in all clinical tumor specimens, the investigator postulates that other mechanisms of resistance to these classes of drugs may be expressed. Tubulins are the targets of the taxanes and vinca alkaloids. Accordingly, the goal of this revised application is to explore other mechanisms of resistance to these agents, with a focus on tubulin genes. In support of this idea, some cell lines selected for resistance to taxol express altered beta-tubulin. The investigator therefore postulates that alterations in tubulin isoform expression, especially changes in relative abundance, are responsible for this form of resistance, and proposes 4 specific aims to test this hypothesis: (1) to determine tubulin isoform expression in non-MDR models of resistance to tubulin-targeted cytotoxins in leukemia, breast and ovarian carcinoma; (2)to study the effects of altered tubulin gene expression on drug sensitivity and microtubule assembly dynamics in transfected cells; (3) to modulate drug sensitivity by down-regulation of specific tubulin gene expression with antisense constructs and oligonucleotides; and (4) to study tubulin isoform expression in tumor specimens obtained from patients before and after therapy with taxanes or vinca alkaloids.