Clinical and Cellular Effects of Interferon alfa 1

使用有限供应的制剂，我们之前在随机双盲比较中评估了干扰素- α 1 （ifn - α 1）与干扰素- α 2的临床效果。ifn - α - 1组不良反应发生率明显低于对照组（p < 0.01）。然而，ifn - α 1对粒细胞计数、NK细胞毒性和ISG的影响与ifn - α 2相当。这些发现表明ifn - α 1可能比ifn - α 2具有更好的耐受性或更高的剂量。通过与上海公共卫生部的合作，生产ifn - α 1的重组DNA现已供应充足。在中国的随机多中心临床试验中，ifn - α 1已被证明对慢性乙型肝炎和丙型肝炎有效。来自中国的数据还表明，ifn - α 1的耐受性优于ifn - α 2。IFN- α 1和IFN- α 2是IFN中主要的α物种。然而，与ifn - α 2相比，ifn - α 1在响应ifn - α 1激活的转录因子复合物中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。除了预期的IFN抗增殖和基因刺激（ISG）作用外，我们还发现了IFN- α 1在骨髓瘤细胞中增加STAT1蛋白表达和诱导凋亡。ifn - α的研究设计有以下目标：a)确认良好的临床耐受性，确定ISG诱导患者的剂量反应特征；b)通过寡核苷酸基因阵列和转录激活因子评估比较ifn - α 2的信号转导和基因调节活性；c)研究骨髓瘤和肾癌的细胞凋亡和基因诱导，以确定临床抗肿瘤活性。由于IFN- α 2的临床应用越来越受到副作用的限制，IFN- α 1在延长lfn - α 2提供的临床线索方面可能特别重要。最后，结果将进一步证实体外抗病毒特异性活性不能预测IFN的其他生物学和临床效应的假设。此外，如果扩大新基因诱导和细胞效应的模式，ifn - α 1可能具有更广泛的反应性临床肿瘤类型。

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.