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SYSTEMIC DELIVERY OF P53 INHIBITS BREAST CANCER

P53 的全身输送可抑制乳腺癌

基本信息

批准号：
6376249
负责人：
ARCHIBALD JAMES MIXSON
金额：
$ 10.03万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-15 至 2002-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6376249
关键词：
angiogenesis angiogenesis inhibitors apoptosis athymic mouse breast neoplasms cell cycle female gene induction /repression gene therapy insulinlike growth factor liposomes neoplasm /cancer genetics neoplasm /cancer therapy neoplastic growth nonhuman therapy evaluation p53 gene /protein reporter genes tumor suppressor genes

项目摘要

DESCRIPTION: (Applicant's Abstract) The applicant has reported that a tumor suppressor gene (p53) complexed to liposomes attenuates the growth of a malignant human breast tumor. In these studies, nude mice, inoculated with breast carcinoma cells, were injected every 10-12 days with a liposome:p53 complex via the tail vein. A marked reduction of greater than 60% in primary tumor volume was observed. Furthermore, it was found that primary tumor size was not only inhibited but regressed in the majority of p53-treated animals. It was also determined that the administration of the liposome:p53 complex reduced the incidence of metastases in these animals. This is the first report for any cancer that demonstrates the effectiveness of gene therapy systemically delivered that has inhibited the primary tumor and its metastases. In this application one of the goals is to determine the mechanism of action of this therapy. Several hypotheses for the reduction of tumor growth by wild-type p53 will be investigated: 1) activation of the apoptotic pathway, 2) inhibition of the cell cycle, and 3) inhibition of angiogenesis. Whether transfected p53 leads to apoptosis or G1 arrest in tissue culture experiments with endothelial and MDA-MB-435 cells will be examined. Investigation of the number of cells in G1 arrest after harvesting the cells from the primary tumor will also be made. Since increased apoptosis in the p53-treated animals were noted in the first study, examination of tumors for the presence and extent of apoptosis will be undertaken. However, instead of using a liposome:p53 complex which is difficult to detect, either a liposome:CAT or liposome:beta-galactosidase gene will be used to determine the distribution. If the liposome:CAT/beta-galactosidase marker does not transfect the tumor cells efficiently, then this suggests that the liposome:p53 complex is acting through a bystander effect. This bystander effect may be due to inhibition of angiogenesis or the induction of IGF-BP3 by p53. In addition, whether p53 and other genes are more effective than p53 alone will be determined.

描述：(申请人摘要)申请人报告了一种肿瘤抑癌基因(P53)与脂质体复合抑制肿瘤细胞的生长恶性人类乳房肿瘤。在这些研究中，裸鼠接种了乳腺癌细胞，每10-12天注射一次脂质体：p53 通过尾静脉的复杂性。年显著减少了60%以上观察原发肿瘤体积。此外，还发现初级的在大多数患者中，肿瘤大小不仅受到抑制，而且还出现了退化用P53处理的动物。该委员会还决定，美国政府脂质体：P53复合体降低了这些动物的转移发生率。这是首个证明其有效性的癌症研究报告。系统地提供了抑制原发肿瘤的基因治疗以及它的转移。在此应用程序中，目标之一是确定这种疗法的作用机制。的几个假说。野生型p53对肿瘤生长的抑制作用将被研究：1) 激活细胞凋亡途径，2)抑制细胞周期，3) 抑制血管生成。转P53基因是否会导致细胞凋亡或内皮细胞和MDA-MB-435在组织培养实验中的G1期停滞将对细胞进行检查。细胞周期G_1期停滞的研究在从原发肿瘤中获取细胞后，也将制造出细胞。自.以来在第一个实验中，用p53处理的动物的细胞凋亡率增加研究，检查肿瘤细胞凋亡的存在和程度将要承担的责任。然而，与使用脂质体：p53复合体不同，很难检测到，无论是脂质体：CAT还是脂质体：β-半乳糖苷酶基因将被用来确定分布。如果脂质体：CAT/β-半乳糖苷酶标记物不能转染肿瘤细胞有效，这表明脂质体：P53复合体正在起作用通过旁观者效应。这种旁观者效应可能是由于抑制血管生成或P53对IGF-BP3的诱导。此外，是否将确定P53和其他基因比单独使用P53更有效。