Arguello F, Sterry J A, Zhao Y Z, Alexander M R, Shoemaker R H, Cohen H J
Division of Cancer Treatment, National Institutes of Health, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702, USA.
Blood. 1996 May 15;87(10):4325-32.
We have investigated human lactate dehydrogenase (LDH) isoenzymes and human nuclear matrix protein 41/7 (NMP 41/7) as potential serologic markers to monitor the course of human leukemia in severe combined immunodeficient (SCID) mice. Following the transplantation of 10(6) human acute lymphoblastic leukemia (ALL) Nalm-6 cells, human specific LDH isoenzymes were measurable in the serum of SCID mice as early as 7 days after transplantation, although serum total LDH increased in some animals as early as 5 days after transplantation. Human NMP 41/7 was measurable in all animals at day 15 after leukemia cell injection. Serum levels of total LDH, human specific LDH and NMP 41/7 increased progressively over time, reaching total LDH levels as high as 50,000 U/L at day 25 after transplantation. To determine whether the levels of LDH and NMP 41/7 in serum were a reflection of human tumor burden, we studied these serologic markers in SCID mice bearing measurable subcutaneous human neuroblastoma tumors, or compared the serum levels of these markers with the number of human leukemia CD10+ cells in the bone marrow of the SCID mice. The serum levels of total LDH, human specific LDH isoenzymes, and NMP 41/7 correlated well with tumor burden, and they drastically decreased or disappeared from serum after the human leukemia or neuroblastoma cells were selectively killed with a single intravenous (IV) injection of 1 to 3 micrograms diphtheria toxin (DT) (the cellular receptor for DT is present on human cells, but not on mouse cells). Paraplegic mice with central nervous system leukemia completely recovered after DT treatment. We conclude that measurements of serum levels of total LDH, human LDH isoenzymes, and NMP 41/7 are sensitive, quantitative, rapid, and easy to perform serologic methods useful to monitor the engraftment, progression, and treatment response of human leukemia in SCID mice.
我们研究了人类乳酸脱氢酶（LDH）同工酶和人类核基质蛋白41/7（NMP 41/7）作为潜在的血清学标志物，以监测严重联合免疫缺陷（SCID）小鼠体内人类白血病的病程。在移植10⁶个人类急性淋巴细胞白血病（ALL）Nalm-6细胞后，早在移植后7天，就可在SCID小鼠血清中检测到人类特异性LDH同工酶，尽管在一些动物中，血清总LDH早在移植后5天就开始升高。在白血病细胞注射后第15天，所有动物均可检测到人类NMP 41/7。血清总LDH、人类特异性LDH和NMP 41/7水平随时间逐渐升高，在移植后第25天，总LDH水平高达50,000 U/L。为了确定血清中LDH和NMP 41/7水平是否反映人类肿瘤负荷，我们在携带可测量皮下人类神经母细胞瘤肿瘤的SCID小鼠中研究了这些血清学标志物，或将这些标志物的血清水平与SCID小鼠骨髓中人类白血病CD10⁺细胞数量进行了比较。血清总LDH、人类特异性LDH同工酶和NMP 41/7水平与肿瘤负荷密切相关，在用1至3微克白喉毒素（DT）单次静脉注射（IV）选择性杀死人类白血病或神经母细胞瘤细胞后，它们在血清中急剧下降或消失（DT的细胞受体存在于人类细胞上，但不存在于小鼠细胞上）。患有中枢神经系统白血病的截瘫小鼠在DT治疗后完全康复。我们得出结论，测量血清总LDH、人类LDH同工酶和NMP 41/7水平是敏感、定量、快速且易于执行的血清学方法，有助于监测SCID小鼠体内人类白血病的植入、进展和治疗反应。
