Maxwell B L, Talpaz M, Gutterman J U
Int J Cancer. 1985 Jul 15;36(1):23-8. doi: 10.1002/ijc.2910360105.
Our interest in studying interferon (IFN) receptor activity in peripheral blood cells (PBCs) from patients with chronic myelogenous leukemia (CML) receiving therapeutic doses of partially purified leukocyte IFN (IFN alpha) stems from a need for more adequate monitoring of IFN therapy. The binding of 35S-labelled recombinant DNA-derived leukocyte clone A IFN (35S-rIFN alpha A) to PBCs from 8 patients with CML was determined before and during IFN alpha treatment. The patients' mean pretherapy binding level (0.049 femtomoles of bound 35S-rIFN alpha A) was in the range of values obtained from 4 normal donors (mean of 0.054 femtomoles bound). Within 24 hr of the first IFN alpha dose, the mean femtomoles bound decreased 10-fold and remained low during the course of IFN alpha treatment. In I/I patient, we demonstrated that this decreased binding was due to a loss in number of IFN receptors. The apparent number of receptors after 5 doses of IFN alpha decreased from approximately 600 receptors per cell at pretherapy to approximately 75 receptors per cell, with no difference in the dissociation constants (1.13 X 10(-10)M, 0.968 X 10(-10)M, before and during treatment, respectively). In 4/4 patients, we demonstrated indirectly that the decreased binding was not due to receptor saturation as a result of residual circulating IFN alpha. In 3/3 patients, we demonstrated a gradual recovery of binding capacity after incubating the patients' PBCs at 37 degrees C. Within 2-7 days in vivo recovery of binding, comparable to pretherapy levels, was observed in 3/3 patients whose IFN alpha therapy was discontinued. Combining all these data, we conclude that in both responding and nonresponding patients with CML, IFN alpha exposure induces decreased binding of labelled IFN when a single recombinant DNA-derived IFN species is used. We feel the supporting data indicate that the decreased binding capacity may be due to receptor down-regulation. In the limited number of patients studied thus far, there was no correlation between clinical hematologic response and occurrence of down-regulation, however, down-regulation of cell surface receptors may be required to sustain a biological effect. Further studies of both the kinetics of down-regulation and activation of key enzyme systems are required to fully evaluate the relevance of these findings.
我们对研究接受治疗剂量部分纯化白细胞干扰素（IFNα）的慢性粒细胞白血病（CML）患者外周血细胞（PBC）中的干扰素（IFN）受体活性感兴趣，这源于更充分监测IFN治疗的需求。在IFNα治疗前和治疗期间，测定了8例CML患者的PBC对35S标记的重组DNA衍生白细胞克隆A干扰素（35S-rIFNαA）的结合情况。患者治疗前的平均结合水平（结合的35S-rIFNαA为0.049飞摩尔）处于从4名正常供体获得的值范围内（平均结合0.054飞摩尔）。在首次给予IFNα剂量后的24小时内，平均结合的飞摩尔数下降了10倍，并且在IFNα治疗过程中一直保持较低水平。在1例患者中，我们证明这种结合减少是由于IFN受体数量的减少。给予5剂IFNα后，受体的表观数量从治疗前的每细胞约600个受体减少到每细胞约75个受体，解离常数在治疗前和治疗期间分别为1.13×10⁻¹⁰M和0.968×10⁻¹⁰M，无差异。在4例患者中，我们间接证明结合减少不是由于残留循环IFNα导致的受体饱和。在3例患者中，我们证明将患者的PBC在37℃孵育后结合能力逐渐恢复。在3例停止IFNα治疗的患者中，在体内2至7天观察到结合恢复到与治疗前水平相当。综合所有这些数据，我们得出结论，在有反应和无反应的CML患者中，当使用单一重组DNA衍生的IFN种类时，IFNα暴露会导致标记的IFN结合减少。我们认为支持数据表明结合能力下降可能是由于受体下调。在迄今为止研究的有限数量患者中，临床血液学反应与下调的发生之间没有相关性，然而，细胞表面受体的下调可能是维持生物学效应所必需的。需要进一步研究下调的动力学和关键酶系统的激活，以充分评估这些发现的相关性。
