Several new approaches to improvement of alpha interferon therapy in chronic myelogenous leukaemia

Shigetaka Asano , Hiromi Ogura , Kenzaburo Tani , Tokiko Inoue , Arinobu Tojo , Keiya Ozawa
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引用次数: 4

Abstract

Several basic experimental and clinical studies were carried out in an attempt to improve the efficacy of alpha interferon therapy for chronic myelogenous leukaemia (CML). First, the combined use of hydroxyurea (HU) and interferon (500–1000 mg daily) in interferon-resistant cases facilitated maintenance of reduced leucocyte production, or a reduction in the dose of interferon, although suppression of Philadelphia chromosome (Ph1)-positive clones was not observed in most cases. In order to try and decrease the rate of lymphoblastic crisis during the course of interferon therapy, we recently added methotrexate (MTX) (10–15 mg, weekly) to the treatment protocol. Since then, no lymphoblastic crisis has been observed. Second, the in vitro expression of alpha interferon-stimulated gene (ISG) mRNA was shown to be markedly decreased in granulocytes of one representative interferon-resistant case, compared to that in granulocytes of the three interferon-sensitive cases. Interestingly, it was found that the transcriptional activity in this case became almost normal when the blood granulocytes were controlled by the addition of HU. These findings suggest that the in vitro transcriptional assay of ISG mRNA may be clinically useful for predicting alpha interferon efficacy. Third, when genetically manipulated, alpha interferon-producing NIH/3T3 cells were co-transplanted using diffusion chambers into nude mice bearing a CML cell line, KU812, the CML tumour growth was shown to be markedly suppressed. This experimental model for alpha interferon replacement gene therapy suggests some directions for future studies on interferon therapy.

改进α干扰素治疗慢性髓性白血病的几种新方法
为了提高α干扰素治疗慢性髓性白血病(CML)的疗效,进行了几项基础实验和临床研究。首先,在干扰素耐药病例中联合使用羟基脲(HU)和干扰素(500 - 1000mg /天)有助于维持减少的白细胞生成,或减少干扰素剂量,尽管在大多数病例中未观察到费城染色体(Ph1)阳性克隆的抑制。为了降低干扰素治疗过程中淋巴细胞危象的发生率,我们最近在治疗方案中加入了甲氨蝶呤(MTX) (10 - 15mg,每周)。从那时起,没有观察到淋巴细胞危象。其次,与3例干扰素敏感病例的粒细胞相比,1例具有代表性的干扰素耐药病例的粒细胞中α干扰素刺激基因(ISG) mRNA的体外表达明显降低。有趣的是,我们发现在加入HU控制血液粒细胞后,这种情况下的转录活性几乎恢复正常。这些发现表明,ISG mRNA的体外转录测定可能在临床上用于预测α干扰素的疗效。第三,通过基因操作,将产生α干扰素的NIH/3T3细胞用扩散室共移植到携带CML细胞系KU812的裸鼠体内,CML肿瘤的生长明显受到抑制。这个α干扰素替代基因治疗的实验模型为今后干扰素治疗的研究提供了一些方向。
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