Dunlop D J, Wright E G, Lorimore S, Graham G J, Holyoake T, Kerr D J, Wolpe S D, Pragnell I B
CRC Beatson Laboratories, Bearsden, Glasgow.
Blood. 1992 May 1;79(9):2221-5.
The proliferative status of the stem cell compartment is thought to be controlled by both positive and negative regulators of proliferation. These regulators have obvious clinical potential in manipulating the integrity and proliferative status of the stem cell in vivo during patient treatment for neoplastic disease. We have tested the ability of the human recombinant homologue of murine macrophage inflammatory protein-1 alpha (rhMIP1 alpha) to suppress the proliferation of primitive murine progenitors in vitro and in vivo. This recombinant protein (stem cell inhibitor, similar to the human homologue of MIP 1 alpha, LD78) is active in a dose-dependent manner in vitro on CFU-S measured at day 12 and to a slightly lesser extent on the more mature CFU-S that are measured at day 8. SCI/rhMIP1 alpha is also active in vivo in two separate models of bone marrow regeneration in which the high proliferative status of the CFU-S compartment is reduced to the quiescent state with a single inoculation of SCI/rhMIP1 alpha. The inhibitory activity of the recombinant protein was then tested in a relevant therapeutic model in which the observed protection of part of the stem cell compartment is reflected by a significant improvement in the kinetics of neutrophil recovery. These results establish the feasibility of testing SCI/rhMIP1 alpha in a range of chemotherapy regimes as a preliminary to clinical trials to attempt to protect the stem cell compartment during treatment for neoplastic disease.
干细胞区室的增殖状态被认为受增殖的正性和负性调节因子控制。这些调节因子在肿瘤疾病患者治疗期间体内操控干细胞的完整性和增殖状态方面具有明显的临床潜力。我们已经测试了鼠巨噬细胞炎性蛋白-1α的人重组同源物（rhMIP1α）在体外和体内抑制原始鼠祖细胞增殖的能力。这种重组蛋白（干细胞抑制剂，类似于MIP 1α的人同源物LD78）在体外对第12天测量的CFU-S呈剂量依赖性活性，对第8天测量的更成熟的CFU-S活性稍低。SCI/rhMIP1α在两种骨髓再生的独立模型中在体内也具有活性，在这些模型中，通过单次接种SCI/rhMIP1α，CFU-S区室的高增殖状态被降低到静止状态。然后在一个相关的治疗模型中测试了重组蛋白的抑制活性，在该模型中，观察到的部分干细胞区室的保护通过中性粒细胞恢复动力学的显著改善得以体现。这些结果确立了在一系列化疗方案中测试SCI/rhMIP1α作为临床试验前奏的可行性，以试图在肿瘤疾病治疗期间保护干细胞区室。
