Clinical and Cellular Effects of Interferon alfa 1

使用限量供应的制剂，我们先前通过随机、双盲对照的方法对干扰素-α1(IFN-α1)进行了临床评估。干扰素-α1的副作用发生率要低得多(p<0.01)。然而，干扰素-α1对粒细胞计数、NK细胞毒性和ISG的影响与干扰素-α2相当。这些发现表明，与干扰素-α2相比，干扰素-α1可能具有更好的耐受性和或更高的剂量。通过与上海卫生部的合作，生产重组DNA的干扰素-α1现已供应充足。在中国的随机、多中心临床试验中，干扰素-α1被证明对慢性乙型和丙型肝炎有效。中国的数据还表明，干扰素-α1比干扰素-α2的耐受性更好。干扰素-α1和干扰素-α2是干扰素的主要种类，通常具有干扰素的特征。然而，与干扰素-α2相比，干扰素-α1在转录因子复合体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。除了预期的干扰素抗增殖和基因刺激(ISG)作用外，我们还发现干扰素-α1增加了STAT1蛋白的表达和诱导骨髓瘤细胞凋亡。设计了以下目标的干扰素-α研究：a)证实良好的临床耐受性，并确定患者ISG诱导的剂量反应特征，B)通过寡核苷酸基因芯片和转录激活因子的评估，比较干扰素-α2的信号转导和基因调控活性；c)研究骨髓瘤和肾癌的细胞凋亡和基因诱导，以证实临床抗肿瘤活性。由于干扰素-α2的临床应用日益受到副作用的限制，干扰素-α1在扩大LFN-α2提供的临床先导方面可能特别重要。最后，结果将进一步证实体外抗病毒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，如果新基因诱导和细胞效应的模式被扩大，干扰素-α1可能会有更广泛的反应临床肿瘤类型。

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.