REDUCED TOXICITY OF TUMOR-TARGETED SALMONELLA

描述：第一阶段：此应用程序专注于小说的开发 靶向实体肿瘤的非致病性细菌载体。这个 研究人员已经设计出了减毒沙门氏菌载体， 在全身给药到荷瘤小鼠后，复制 肿瘤内的四个数量级，最小复制 邻近的正常组织。初步研究表明，这种方法是 在减缓肿瘤生长和延长生存方面都有效，而且 适用于多种癌症的治疗，包括肺癌， 乳房、肝脏、肾脏、结肠癌和黑色素瘤。这些向量被衰减了 通过营养缺乏性突变限制其在正常组织中的发病。 细菌在体内使用的另一个令人担忧的问题是它们能否 诱导肿瘤坏死因子-α(TNF-α)介导的感染性休克。这个 研究人员现在已经在沙门氏菌中分离出一种突变，它可以改变 脂质A涂层，从而减少了肿瘤坏死因子-α的诱导，但保留了肿瘤- 这些细菌在体内的靶向性和抗肿瘤活性。为了 培养出没有感染性休克的细菌菌株，并完全 在减重后，研究人员建议探索这种脂质的用途 突变与营养缺乏性突变相结合，产生一种 将进行肿瘤靶向和抗肿瘤测试的营养缺乏症 在至少两个实体肿瘤模型中的活性。这些研究将导致 具有强大抗肿瘤活性的全减毒沙门氏菌载体 既针对原发肿瘤又针对转移部位。 建议的商业应用：不可用

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