EVALUATION OF CHEMICAL MYELOTOXICITY USING AN IN VIVO LEUKEMIA TRANSPLANT MODEL

使用体内白血病移植模型评估化学骨髓毒性

• 批准号: 3876856
• 负责人: M P DIETER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3876856
• 关键词: acetaminophen; antileukemic agent; chemical carcinogen; chemical carcinogenesis; chemical structure function; diol; ethylene glycols; health care model; laboratory rat; leukemia; model design /development; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation

Spontaneous mononuclear cell leukemia is a confounding factor in evaluating chemical leukemogenicity in the NTP 2-year carcinogenicity studies. A short-term assay for F344 rat leukemia was developed to better discriminate between age-induced and chemically-enhanced leukemia. The accuracy and sensitivity of the transplant model for predicting the long-term leukemogenic potency of chemicals was confirmed in short-term assays with 7 chemicals that had increased or decreased the prevalence of leukemia in previous 2-year carcinogenicity studies. Additional studies with the short-term assay revealed structure-activity relationships for chemicals that were either negative or positive for leukemic trends. Nine different glycol ethers were evaluated in the short-term assay for anti-leukemic activity. Of these, only ethylene glycol monomethyl ether and ethylene glycol monoethyl ether exhibited chemotherapeutic potential. Ethylene glycol monomethyl ether was a more potent antileukemic agent than the monoethyl ether, and at non-toxic doses in drinking water completely eliminated the early manifestations of leukemia, prevented early mortality, and doubled the tumor latency period. These data were confirmed by in vitro tests with suspended leukemic cell cultures. Presently, the chemotherapeutic potential for the acid and aldehyde metabolites of ethylene glycol monomethyl ether, as well as chemicals in the propylene glycol monomethyl glycol alkyl ether series, are being evaluated. By contrast, two chemicals containing dimethyl esters of phosphoric acid (dichlorvos and trichlorfon) enhanced the expression of leukemia in the short-term assay and in 2-year carcinogenicity tests. Three other chemicals with the same structural relationship: dimethyl hydrogen phosphite, dimethyl methylphosphonate, and dimethylmorpholinophosphoramidate also increased the incidence of leukemia in recently completed 2-year studies. These observations suggest that the dimethyl phosphoric acid ester moiety should be considered a structural alert for leukemogenicity. Presently, the leukemogenic potential of acetaminophen is being evaluated in the short-term leukemia transplant model to confirm and extend the observations obtained from 2-year studies.

自发性单核细胞白血病是评估的一个混杂因素 NTP 2年致癌性研究中的化学致白血病作用。一个 为了更好地区分F344大鼠白血病，建立了一种短期检测方法 年龄诱发白血病和化学增强型白血病之间的关系。精确度和 移植模型预测远期疗效的敏感性 化学物质的致白血病效力在短期试验中得到证实，有7 增加或降低白血病患病率的化学物质 之前两年的致癌性研究。其他研究与 短期分析揭示了化学物质的结构-活性关系 白血病趋势呈阴性或阳性的患者。九种不同的 乙二醇醚在短期抗白血病试验中被评价。 活动。其中，只有乙二醇单甲醚和乙烯 乙二醇单乙醚具有潜在的化疗潜力。乙烯 乙二醇单甲醚是比阿司匹林更有效的抗白血病药物 单乙醚，并在饮用水中完全无毒剂量 消除了白血病的早期表现，防止了早期死亡， 并将肿瘤潜伏期延长了一倍。这些数据得到了In的确认 悬浮白血病细胞培养的体外试验。目前， 沙门氏酸和乙醛代谢产物的化学治疗潜力 乙二醇单甲醚以及丙烯中的化学物质 乙二醇单甲基乙二醇烷基醚系列，正在评估中。通过 相比之下，两种含有磷酸二甲酯的化学物质 敌敌畏和敌百虫促进白血病细胞的表达 短期化验和为期两年的致癌试验。另外三个 具有相同结构关系的化学品：二甲基氢 亚磷酸酯、甲基亚磷酸二甲酯和 二甲基吗啉磷酰胺也增加了白血病的发病率 在最近完成的两年研究中。这些观察结果表明， 二甲基磷酸酯部分应被认为是一种结构 警惕白血病的致病性。目前，白血病的潜在致病能力 扑热息痛正在接受短期白血病移植的评估 模型来确认和扩展从两年的研究中获得的观察结果。