LOSS OF TUMORGENICITY INDUCED BY TGF-B ANTISENSE GENE

TGF-B 反义基因诱导的致瘤性丧失

• 批准号: 2700652
• 负责人: EMMANUEL T. AKPORIAYE
• 金额: $ 17.52万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700652
• 关键词: RNase protection assay; T lymphocyte; angiogenesis; antineoplastics; antisense nucleic acid; breast neoplasms; chemical synthesis; disease /disorder model; drug screening /evaluation; gene expression; gene induction /repression; immunosuppression; immunosuppressive; interferon gamma; laboratory mouse; loss of heterozygosity; macrophage; messenger RNA; metastasis; neoplasm /cancer immunology; neoplasm /cancer vaccine; neoplastic cell; neoplastic growth; neoplastic process; transfection; transforming growth factors; transposon /insertion element; vector vaccine

DESCRIPTION: (Applicant's Abstract) Lymphoid infiltration of mammary tumors has been considered evidence of a host anti-tumor immune response. The progression of tumor despite the presence of these immune cells has been attributed to the production of immunosuppressive substances such as transforming growth factor-beta (TGF-beta) within the tumor. In breast cancer patients, the presence of tumor-derived TGF-beta-1 directly correlates with disease progression, metastases and disease recurrence. Transforming growth factor is a cytokine produced by many cell types including malignant cells and is a potent inhibitor of immune functions. A potentially effective form of tumor-specific immunotherapy of cancer is one in which tumor vaccines consisting of tumor cells deprived of the ability to synthesize TGF-beta are used. The objective of this study is to inhibit the production of TGF-beta in mammary tumor cells by genetic manipulation and to employ these gene modified cells as vaccines to treat established tumors and eradicate residual metastatic disease. TGF-beta synthesis will be blocked by inserting an antisense TGF-beta transcriptional cassette in mammary tumor cells to produce complementary RNA that binds endogenous messenger TGF-beta RNA to prevent its translation to protein. The specific aims of this research are to determine: (1a) The efficacy of antisense TGF-beta tumor cell vaccines in eliminating established primary tumors and residual metastatic disease. (1b) The ability of IFN-gamma or B7.1 gene transfer to improve the effectiveness of antisense TGF-beta tumor vaccines. (2) The mechanism by which antisense TGF-beta gene expression inhibits tumorigenicity. The results from this study will demonstrate the effectiveness of antisense TGF-beta tumor vaccines in treating established tumors and eradicating metastatic disease and the ability of IFN-gamma and B7.1 to potentiate antitumor activity. These studies will lead to the development of a novel and effective approach of treating metastatic breast cancer which has immediate application in the clinic. In the long term, it is expected that this approach of genetically eliminating tumor-derived immunosuppression in order to trigger an effective antitumor response will find widespread use in treating other forms of cancer.

描述：（申请人的摘要）乳腺肿瘤的淋巴浸润 已被认为是宿主抗肿瘤免疫反应的证据。 这 尽管存在这些免疫细胞，但肿瘤的进展一直是 归因于免疫抑制物质的产生，例如 转化肿瘤内生长因子β（TGF-β）。 在乳房中 癌症患者，直接存在肿瘤衍生的TGF-beta-1 与疾病进展，转移和疾病复发有关。 转化生长因子是由许多细胞类型产生的细胞因子 包括恶性细胞，是免疫功能的有效抑制剂。 一个 癌症肿瘤特异性免疫疗法的潜在有效形式是一种 其中由肿瘤细胞组成的肿瘤疫苗剥夺了能力 使用合成的TGF-β。 这项研究的目的是抑制 通过遗传操纵和TO在乳腺肿瘤细胞中产生TGF-β 用这些基因修饰细胞作为疫苗来治疗已建立的肿瘤，并且 消除残留转移性疾病。 TGF-β合成将被阻止 通过在乳腺肿瘤中插入反义TGF-beta转录盒 细胞产生结合内源信使tgf-beta的互补RNA RNA以防止其转化为蛋白质。 这个特定的目的 研究将确定：（1a）反义TGF-β肿瘤的功效 细胞疫苗消除已建立的原发性肿瘤和残留 转移性疾病。 （1B）IFN-GAMMA或B7.1基因转移至 提高反义TGF-β肿瘤疫苗的有效性。 （2） 反义TGF-β基因表达抑制的机制 肿瘤性。 这项研究的结果将证明 反义TGF-β肿瘤疫苗在治疗已建立的有效性 肿瘤和根除转移性疾病以及IFN-GAMMA和 B7.1增强抗肿瘤活性。 这些研究将导致 开发一种新颖有效的治疗转移性乳房的方法 在诊所中立即应用的癌症。 从长远来看 可以预期这种遗传消除肿瘤衍生的方法 免疫抑制以触发有效的抗肿瘤反应 在治疗其他形式的癌症中找到广泛使用。