PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

大鼠乳腺和小鼠肺模型中基因表达变化的比较 在人类中的表达改变和基因表达调控 已知的化学预防药物。遗传的极大的不稳定性，如 反映在杂合性缺失或非整倍体中，似乎是大多数人类的特征 癌症，甚至许多浸润性前病变，如乳房的DCIS、发育不良 肺、结肠腺瘤、宫颈CIN 2、CIN 3等病变 对比更有限数量的癌基因或抑癌基因 [P53，Ki Ras，APC，Rb等]已完全表征为可能 突变和大多数癌症的特征是有限数量的 这些相同基因的突变。这项研究的目的是使用 允许同时检测改变的RNA的方法学 同时在数百个基因中的水平，这另外还允许 一种是克隆并对编码这些基因的cDNA进行部分测序 以一种相对容易的方式表达基因。大鼠乳腺肿瘤模型正在建立 用于容易地确定有效的化学预防药物是否会改变 筛选模式中识别的假定RNA的水平。1) MNU大鼠乳腺肿瘤基因表达变化的广泛筛查 各种RNA 2)使用更有限的RNA子集进行比较(40-50) MNU诱导的大鼠乳腺肿瘤中这些基因表达的改变， DMBA与辐射加雌二醇诱发的肿瘤 使用有限数量的RNA，无论人们是否看到 不同模式的MNU诱发的HARA基因突变肿瘤 致癌与未携带HARAS癌基因突变的肿瘤 4)确定使用RNA的子集是否表达这些 基因受已知的化学预防药物的调节。

Altered Genes Expression In Rat Mammary And Mouse Lung Models: Comparison With Altered Expression In Humans And Modulation of Gene Expression by Known Chemopreventive Agents. Substantial genetic instability, as reflected in LOH or aneuploidy, appear to be a hallmark of most human cancers and even many preinvasive lesions, e.g. DCIS in breast, dysplastic lesions in lung, colon adenomas, CIN 2 and CIN 3 in cervix etc. In contrast a more limited number of oncogenes or tumor suppressor genes [P53, Ki Ras, APC, Rb etc] have been fully characterized for possible mutations and most cancers are characterized for a limited number of mutations in these same genes. The objective of this study is to use methodologies which allow the simultaneous examination of altered RNA levels in hundreds of genes simultaneously and which additionally allows one to clone and perform partial sequencing of the cDNAs coding for these genes in a relatively easy manner. The rat mammary tumor model is being used to readily determine whether effective chemopreventive agents alter levels of the presumptive RNAs identified in the screening mode. 1) Extensive screening of MNU rat mammary tumors for altered expression of various RNAs 2) Compare using a more limited subset of RNAs (40-50) altered expression of these genes in rat mammary tumors induced by MNU, DMBA and tumors induced by radiation plus estradiol 3) Determine again employing a limited number of RNAs whether one sees a substantially different pattern in MNU induced tumors bearing a mutation in the HaRas oncogeny versus those tumors not bearing a mutation in the HaRas oncogene 4) Determine employing a subset of RNAs whether the expression of these genes is modulated by known chemopreventive agents.