Clinical and Cellular Effects of Interferon alfa 1

干扰素 α 1 的临床和细胞效应

• 批准号: 6780933
• 负责人: ERNEST C BORDEN
• 金额: $ 31.75万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780933
• 关键词: MHC class II antigen; apoptosis; biological signal transduction; cell growth regulation; clinical trial phase I; gene induction /repression; human subject; human therapy evaluation; interferon alpha; metastasis; monocyte; multiple myeloma; neoplasm /cancer immunotherapy; northern blottings; patient oriented research; renal cell carcinoma

Using a preparation that was in limited supply, we previously assessed Interferon-alpha 1 (IFN-alpha 1) clinically in a randomized, double blind comparison to IFN-alpha 2. The frequency of side effects was much less with IFN-alpha1 (p less than 0,01). Yet effects of IFN-alpha 1 on granulocyte counts, NK cell cytotoxicity, and an ISG were comparable to IFN-alpha2. These findings suggest that IFN-alpha 1 might be given with better tolerance and or higher doses than IFN-alpha 2. Recombinant DNA produced IFN-alpha 1 has now come available in adequate supply through a collaboration with the Ministry of Public Health in Shanghai. In randomized, multi-center clinical trials in China, IFN-alpha 1 has proven effective for chronic hepatitis B and C. Data from China also suggests IFN-alpha 1 is better tolerated than IFN-alpha 2. IFN-alpha 1, together with IFN-alpha 2, is a predominant IFN-alpha species generally characteristic of an IFN. However, IFN-alpha 1 has differing receptor binding affinities and differing cross species antiviral activity differences in the transcription factor complexes activated in response to IFN-alpha 1 as compared to IFN-alpha 2. In addition to expected IFN antiproliferative and gene stimulatory (ISG) effects, we have also identified an increase in STAT1 protein expression and induction of apoptosis in myeloma cells by IFN-alpha 1. Studies of IFN-alpha have been designed with the following goals: a) confirm good clinical tolerance and define the dose response characteristics of ISG induction in patients, b) compare the signal transducing and gene modulatory activity to those of IFN-alpha 2 by oligonucleotide gene array and assessment of transcription activating factors, c) study apoptosis and gene induction in myeloma and renal carcinoma to confirm clinical antitumor activity. Since expanded clinical use of IFN- alpha 2 has increasingly been limited by side effects, IFN-alpha 1 may be particularly important in extending clinical leads provided by LFN-alpha 2. Finally, results will further confirm the postulate that antiviral specific activity in vitro does not predict for other biological and clinical effects of IFN. In addition, if the pattern of novel gene induction and cellular effects are expanded, IFN-alpha 1 could have a broader spectrum of responsive clinical tumor types.

使用有限供应的制剂，我们先前在临床上评估了干扰素-α 1（IFN-α 1）与IFN-α 2的随机、双盲比较。 IFN-α 1的副作用频率要低得多（p <0.01）。 然而，IFN-α 1对粒细胞计数、NK细胞毒性和ISG的作用与IFN-α 2相当。 这些发现表明，IFN-α 1可能比IFN-α 2具有更好的耐受性和/或更高的剂量。 通过与上海公共卫生部的合作，重组DNA生产的IFN-α 1现已获得充足的供应。 在中国的随机多中心临床试验中，IFN-α 1已被证明对慢性B和C型肝炎有效。 来自中国的数据也表明IFN-α 1比IFN-α 2耐受性更好。IFN-α 1与IFN-α 2一起是IFN的主要特征性IFN-α种类。 然而，与IFN-α 2相比，IFN-α 1具有不同的受体结合亲和力和不同的跨物种抗病毒活性差异，其在响应于IFN-α 1活化的转录因子复合物中。 除了预期的干扰素抗增殖和基因刺激（ISG）的影响，我们还确定了STAT 1蛋白表达的增加和诱导骨髓瘤细胞的细胞凋亡的IFN-α 1。IFN-α的研究设计有以下目标：a）确认良好的临床耐受性并确定患者中ISG诱导的剂量反应特征，B）通过寡核苷酸基因阵列和评估转录激活因子比较IFN-α 2的信号转导和基因调节活性，c）研究骨髓瘤和肾癌中的细胞凋亡和基因诱导以确认临床抗肿瘤活性。 由于IFN-α 2的扩大临床使用越来越受到副作用的限制，IFN-α 1在扩展由LFN-α 2提供的临床引导中可能特别重要。 最后，结果将进一步证实体外抗病毒比活性不能预测干扰素的其他生物学和临床作用的假设。 此外，如果新的基因诱导和细胞效应的模式得到扩展，IFN-α 1可能具有更广泛的响应性临床肿瘤类型。