EVALUATION OF CHEMICAL MYELOTOXICITY USING AN IN VIVO LEUKEMIA TRANSPLANT MODEL

在NTP 2中使用的高达30%的Fischer 344/N品系大鼠- 一年毒性和致癌性研究自发发展 白血病开始于大约18个月，这降低了 检测化学性白血病的敏感性。An In 体内细胞移植模型被开发用于转移白血病 脾细胞从自发性白血病大鼠转化为幼鼠， 健康受体大鼠。本病白血病发病后表现 取自这些大鼠的脾细胞再次用于移植 体内维持白血病细胞系。形态上的和 移植后器官和细胞的生化反应 老鼠的特征是更好地区分年龄- 诱发和化学强化的白血病。肿瘤 自发性和移植性病例的形态结构 相同，但肿瘤表达的时间缩短了 从18个月到2个月不等。苹果酸活性的变化 脱氢酶、葡萄糖-6-磷酸脱氢酶和 白血病血液和脾组织中的乙酰胆碱酯酶 单核细胞提供了始终如一和明确的 白血病的生化证据先于其他常见临床 疾病的征兆。这些肿瘤标志物酶证明了 白血病病程中的进行性变化 与疾病的严重程度有关。法律程序的有效性 阿司匹林长期致白血病效力预测模型的建立 化学物质是通过进行短期研究来证明的 分别含有2-乙氧基乙醇和吡啶的化学品 在过去的两年中，白血病的发病率下降和增加 每年进行致癌性测试。类似的研究也在进行中 额外的正性和负性致白血病化学物质 确认白血病移植模型可以检测到 含有致癌活性的化学品中是否存在致癌活性 结构差异，并提供有效的数据库基础 未来的调查。

Up to 30% of the Fischer 344/N strain of rats used in the NTP 2- year toxicity and carcinogenicity studies develop spontaneous leukemia commencing at about 18 months, which reduces the sensitivity for the detection of chemical leukemogenesis. An in vivo cell transplant model was developed to transfer leukemic spleen cells from a rat with spontaneous leukemia into young, healthy recipient rats. After expression of the disease leukemic spleen cells from those rats were again used for transplantation to maintain the leukemic cell line in vivo. The morphological and biochemical responses in organs and cells from the transplanted rats were characterized to better discriminate between age- induced and chemically-enhanced leukemia. The tumor morphology in the spontaneous and transplanted cases was identical, but the time to expression of the tumor was reduced from 18 months to 2 months. Changes in the activities of malate dehydrogenase, glucose-6-phosphate dehydrogenase, and acetylcholinesterase from the leukemic blood and spleen mononuclear cells provided consistent and unequivocal biochemical evidence of leukemia prior to other common clinical signs of the disease. These tumor marker enzymes demonstrated progressive changes in the course of leukemia that were directly associated with the severity of the disease. The validity of the model for predicting the long-term leukemogenic potency of chemicals was demonstrated by conducting short-term studies with 2-ethoxyethanol and pyridine, chemicals that respectively decreased and increased the incidence of leukemia in previous 2- year carcinogenicity tests. Similar studies are underway with additional positive and negative leukemogenic chemicals to confirm that the leukemia transplant model could detect both the presence and absence of carcinogenic activity in chemicals with structural dissimilarities, and to provide a valid data base for future investigations.