MODIFIED TNF-ALPHA: AN ANTI CANCER THERAPY

描述(由申请人提供)：建议的长期目标 正在研究开发有效的抗癌药物，修饰人类 肿瘤坏死因子-α(HTNFas)。TnFa是一种有效的抗肿瘤药物 但它的治疗应用因其重要的一面而受到限制。 效果。然而，可以对TNFa进行修饰，以保持其抗肿瘤作用 活动的同时，其有害影响也减少了。这已经是 用聚乙烯诱变TNFa和衍生TNFa 乙二醇(聚乙二醇酯)。这项建议侧重于描述和比较 突变型和野生型hTNFas经20 kDa修饰。 具体目标是： 1)对聚乙二醇-hTNFas进行药理学表征、毒性分析 单次大剂量的聚乙二醇化肿瘤坏死因子和延长的聚乙二醇化的肿瘤坏死因子治疗； 2)定义TNFa抗癌特征，分析：a)抗肿瘤效果 同基因和裸鼠的B16黑色素瘤，b)聚乙二醇hTNFas的亲和力 人肿瘤坏死因子受体I和II(临床试验的先决条件)； 3)测定这些聚乙二醇-hTNFas的抗人肿瘤效果，治疗 荷人结肠癌的无瘤小鼠。 建议的商业应用： 这项建议的重点是开发新的治疗剂，聚乙二醇hNTFas 对多种实体肿瘤有效。改性人肿瘤坏死因子的新性质 包括与细胞毒性化疗药物有显著协同作用的可能性 以及靶向肿瘤血管和宿主免疫系统的可能性。

DESCRIPTION (PROVIDED BY APPLICANT): The long-term goal of the proposed research is the development of effective anti-cancer agents, modified human tumor necrosis factor-alphas (hTNFas). TNFa is a potent anti-neoplastic agent but its therapeutic application has been limited by its significant side effects. However, TNFa can be modified so that it retains its anti-tumor activities while its deleterious effects are reduced. This has been accomplished by mutation of TNFa and derivitization of TNFa with polyethylene glycol (PEG). This proposal focuses on the characterization and comparison of mutant and wild hTNFas modified with 20 kDa PEGs. The specific aims are to: 1) pharmacologically characterize the PEG-hTNFas, toxicity analyses after a single high dose of PEG-TNFa and a prolonged PEG-TNFa treatment; 2) define TNFa anti-cancer features, analyses of: a)anti-tumor efficacies in syngeneic and athymic mice with B16 melanomas, b)affinities of the PEG- hTNFas for hTNF receptors I and II (prerequisite for clinical trials); and 3) determine the anti-human tumor efficacies of these PEG-hTNFas, treatment of athymic mice bearing human colon carcinomas. PROPOSED COMMERCIAL APPLICATION: This proposal focuses on the development of new therapeutic agents, PEG-hNTFas effective against a wide range of solid tumors. Novel geatures of modified hTNFas include the likelihood of a marked synergy with cytotoxic chemotherapeutic agents and the potential to target the tumor vasculature and the host immune system.