REDUCED TOXICITY OF TUMOR-TARGETED SALMONELLA

降低针对肿瘤的沙门氏菌的毒性

• 批准号: 2728391
• 负责人: DAVID G BERMUDES
• 金额: $ 10万
• 依托单位: VION PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2728391
• 关键词: Salmonella; antineoplastics; attenuated microorganism; disease /disorder model; gene mutation; laboratory mouse; lipids; neoplasm /cancer therapy; protein engineering; transfection /expression vector; tumor necrosis factor alpha

DESCRIPTION: Phase I: This application focuses on development of novel nonpathogenic bacterial vectors for targeting solid tumors. The investigators have engineered attenuated Salmonella vectors which, following systemic administration into tumor-bearing mice, replicate over four orders of magnitude within tumors, with minimal replication in adjacent normal tissues. Initial studies have shown that this method is effective at both slowing tumor growth and prolonging survival, and is applicable to the treatment of a variety of cancers, including lung, breast, liver, kidney, colon and melanoma. These vectors were attenuated by auxotrophic mutations which limit their pathogenesis in normal tissues. A further concern for the in vivo use of bacteria is their ability to induce tumor necrosis factor-alpha (TNF-alpha)-mediated septic shock. The investigators have now isolated a mutation in Salmonella which alters the lipid A coat, thereby reducing TNF-alpha induction, yet retains the tumor- targeting and antitumor activity of these bacteria in vivo. In order to develop strains of bacteria that are devoid of septic shock and are fully attenuated, investigators propose to explore the use of this lipid mutation in combination with auxotrophic mutations to generate a variety of auxotrophies which will be tested for tumor-targeting and antitumor activity in at least two solid tumor models. These studies will result in fully attenuated Salmonella vectors with potent antitumor activity capable of targeting both the primary tumors and metastatic sites. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述：第一阶段：本申请侧重于开发新的 用于靶向实体瘤的非致病性细菌载体。的 研究者已经改造了减毒沙门氏菌载体， 在全身给药到荷瘤小鼠中后， 在肿瘤内的四个数量级， 邻近的正常组织。初步研究表明，这种方法 有效减缓肿瘤生长和延长生存期， 适用于治疗多种癌症，包括肺癌， 乳腺、肝脏、肾脏、结肠和黑素瘤。这些载体被削弱了 营养缺陷型突变限制了它们在正常组织中的发病机制。 细菌体内应用的另一个问题是它们的能力， 诱导肿瘤坏死因子-α（TNF-α）介导脓毒性休克。的 研究人员现在已经分离出沙门氏菌的一种突变， 脂质A包被，从而减少TNF-α诱导，但保留肿瘤- 这些细菌在体内的靶向和抗肿瘤活性。为了 培养出没有感染性休克的细菌菌株， 研究人员建议探索这种脂质的用途 突变与营养缺陷型突变组合以产生多种 将用于肿瘤靶向和抗肿瘤测试的营养缺陷型 在至少两种实体瘤模型中的活性。这些研究将导致 具有有效抗肿瘤活性的完全减毒沙门氏菌载体 同时针对原发肿瘤和转移部位。 拟议商业应用：不可用