In vivo inhibition of the development of myeloid leukemia by injection of macrophage‐and granulocyte‐inducing protein
In vivo inhibition of the development of myeloid leukemia by injection of macrophage‐and granulocyte‐inducing protein
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通过注射巨噬细胞和粒细胞诱导蛋白体内抑制髓系白血病的发展
DOI：
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发表时间：
1981
影响因子：
6.4
通讯作者：
L. Sachs
中科院分区：
文献类型：
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作者：
J. Lotem;L. Sachs
结果表明，注射巨噬细胞和粒细胞诱导蛋白(MGI)可在体内抑制髓系白血病的发展，并刺激正常的骨髓生成。注射的MGI包括MGI-1活性和MGI-2活性，MGI-1活性可诱导正常成髓细胞集落形成，MGI-2活性可诱导正常和MGI+D+白血病成髓细胞分化为成熟的巨噬细胞或粒细胞。注射的MGI制剂不含干扰素，结果表明，所获得的结果不是由于微量污染的脂多糖(LPS)造成的。腹腔注射MGI可刺激正常成年小鼠的骨髓生成。注射MGI可显著提高血清MGI活性水平，而注射内毒素可刺激体内MGI的产生。给静脉接种MGI+D+或MGI+D−髓系白血病细胞的小鼠注射MGI，治疗3周后，骨髓中白血病集落形成细胞数量减少3~5倍，成熟粒细胞增加，骨髓和外周血中形态鉴定的髓母细胞百分比减少2~5倍。接种MGI+D+细胞的MGI处理组小鼠剩余的白血病集落形成细胞不抵抗MGI-2的诱导分化。注射脂多糖对接种耐内毒素的MGI+D-−白血病细胞的小鼠也有抑制作用，但这种抑制作用不如MGI，可能是间接的。注射MGI使皮下接种白血病细胞的小鼠的肿瘤体积减少至少50倍。静脉接种MGI+D+细胞或皮下接种MGI+D-−细胞组小鼠的中位生存期延长约40%，皮下接种MGI+D+细胞组小鼠50%未发生肿瘤。MGI还可增强环磷酰胺的抗肿瘤作用。注射的MGI制剂的白血病抑制活性与羟基磷灰石柱层析出的MGI活性峰值有关，并在破坏MGI-2活性的温度下处理而被破坏。这表明MGI-2对白血病的抑制作用是由MGI-2介导的。建议改进MGI的治疗方案，无论是否使用细胞毒治疗的化合物，都应该能够更好地抑制白血病的发展，这些结果也应该适用于人类髓系白血病的治疗。
It is shown that injection of macrophage‐ and granulocyte‐inducing protein (MGI) can inhibit the development of myeloid leukemia in vivo and stimulate normal myelopoiesis. The MGI injected contained MGI‐1 activity that induces colony formation with normal myeloblasts, and MGI‐2 activity that induces differentiation of normal and MGI+D+ leukemic myeloblasts to mature macrophages or granulocytes. The MGI preparations injected did not contain interferon and it was shown that the results obtained were not due to minute amounts of contaminating lipopolysaccharide (LPS). Intraperitoneal injection of MGI stimulated myelopoisesis in normal adult mice. Markedly higher levels of serum MGI activity could be obtained by injecting MGI than by injecting LPS, a compound that stimulates the in vivo production of MGI. Injection of MGI into mice that had been inoculated intravenously with MGI+D+ or MGI+D− myeloid leukemic cells showed that, 3 weeks after the beginning of treatment, there was a 3‐ to 5‐fold decrease in the number of leukemic colony‐forming cells and an increase in mature granulocytes in the bone marrow, together with a 2‐ to 5‐fold decrease in the percentage of morphologically identified myeloid blast cells in the bone marrow and peripheral blood. The remaining leukemic colony‐forming cells in the MGI‐treated mice inoculated with MGI+D+ cells were not resistant to the induction of differentiation by MGI‐2. Injection of LPS to mice inoculated with LPS‐resistant MGI+D− leukemic cells also inhibited the development of leukemia, but this inhibition was less effective than with MGI and was presumably indirect. Injection of MGI reduced the tumor volume in mice subcutaneously inoculated with leukemic cells at least 50‐fold. The median survival time of MGI‐treated mice inoculated intravenously with MGI+D+ cells or subcutaneously with MGI+D− cells was increased by about 40%, and 50% of the MGI‐treated mice inoculated subcutaneously with MGI+D+ cells did not develop tumors. MGI also increased the anti‐tumor effect of cyclophosphamide. The leukemia‐inhibiting activity in the injected MGI preparations was associated with the peak of MGI activity separated on a hydroxylapatite column and was destroyed by treatment at the temperature which destroys MGI‐2 activity. This indicates that the inhibition of leukemia development was mediated by MGI‐2. It is suggested that improved schedules of MGI treatment, with or without compounds used in the cytotoxic types of therapy, should be able to give an even better inhibition of leukemia development and that these results should also be applicable to the therapy of human myeloid leukemia.