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：该应用程序重点开发新颖的 用于靶向实体瘤的非致病性细菌载体。这 研究人员设计了减毒沙门氏菌载体， 对荷瘤小鼠全身给药后，复制 肿瘤内四个数量级，在肿瘤内复制极少 邻近的正常组织。初步研究表明该方法 可以有效减缓肿瘤生长并延长生存期 适用于治疗多种癌症，包括肺癌、 乳腺癌、肝脏、肾脏、结肠癌和黑色素瘤。这些载体被削弱了 通过营养缺陷型突变限制其在正常组织中的发病机制。 对细菌体内使用的进一步关注是它们的能力 诱导肿瘤坏死因子-α（TNF-α）介导的感染性休克。这 研究人员现已分离出沙门氏菌的突变，该突变改变了 脂质 A 涂层，从而减少 TNF-α 诱导，但保留了肿瘤- 这些细菌在体内的靶向和抗肿瘤活性。为了 开发出不发生感染性休克且完全 减弱，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相结合，产生多种 将测试肿瘤靶向和抗肿瘤的营养缺陷型 在至少两种实体瘤模型中具有活性。这些研究将导致 完全减毒的沙门氏菌载体，具有有效的抗肿瘤活性 靶向原发性肿瘤和转移部位。 拟议的商业应用：不可用