MECHANISMS REGULATING REVERSAL OF PREMALIGNANCY

描述：(改编自调查人员的摘要)远景目标： 建立可用于治疗癌前病变的治疗方法 疾病。逆转癌前疾病是癌症预防的目标之一 治疗方案。在早期阶段中断恶性过程是 比治疗完全发展的，也许是转移性的癌症更可取。 虽然在确定逆转糖尿病的治疗药物方面取得了进展 人类的恶性，调查仍在继续。以机制为基础的临床前和 临床研究被用来确定可治疗的癌前病变和 最合适的基因和细胞靶点。 这项研究将测试特定的遗传机制的作用可能 利用一种独特的转基因技术逆转癌前疾病 癌症发展的小鼠模型。在此模型中， 启动癌蛋白(猿猴病毒SV40T抗原(Tag))是有条件的 受四环素反应基因表达调控(TET反应) 系统并通过小鼠乳腺肿瘤病毒Long靶向上皮细胞 终端重复(MMTV-LTR)。当癌蛋白的表达终止时 四个月后，增生症逆转。相反，当癌蛋白 表达在七个月后终止，增生没有逆转 找到了。可以转移到肺部的腺癌在9点之间发展。 12个月龄时，标签的表达没有中断。 该提案的具体成果：1)确定P53和Bax是否 诱导是成功逆转的关键遗传途径 在整个动物中都是癌前疾病。2)确定为什么 在这个模型中，癌症进展早期的中介逆转不能 促进后期的反转。

DESCRIPTION: (Adapted from the investigator's abstract) Long-range objective: Establish therapeutic approaches that can be used to treat preneoplastic disease. Reversal of premalignant disease is one goal of cancer prevention treatment programs. Interruption of the malignant process at an early stage is preferable to treating the fully developed, and perhaps metastatic, cancer. While inroads have been made in identifying therapeutic agents for reversal of human malignancy, investigations continue. Mechanism-based preclinical and clinical studies are utilized to identify stages of treatable premalignancy and the most appropriate genetic and cellular targets. This study will test the role of specific genetic mechanisms possibly responsible for reversal of premalignant disease utilizing a unique transgenic mouse model of cancer development. In this model temporal expression of the initiating oncoprotein (Simian Virus SV40 T Antigen (TAg)) is conditionally regulated by the tetracycline responsive gene expression (tet responsive) system and directed to epithelial cells by the mouse mammary tumor virus long terminal repeat (MMTV-LTR). When expression of the oncoprotein is terminated after four months, hyperplasia reverses. In contrast, when oncoprotein expression is terminated after seven months, no reversal of hyperplasia is found. Adenocarcinomas that can metastasize to the lung develop between nine and twelve months of age when TAg expression is not interrupted. Specific accomplishments for this proposal: 1) Establish if p53 and Bax induction are critical genetic pathways for the successful reversal of premalignant disease in the whole animal. 2) Determine why pathways that mediate reversal at an early stage of cancer progression in this model cannot promote reversal at a later stage.