Dieter M P, Jameson C W, Maronpot R R, Langenbach R, Braun A G
National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Cancer Chemother Pharmacol. 1990;26(3):173-80. doi: 10.1007/BF02897195.
Structure-activity studies with nine glycol alkyl ethers were conducted with a cellular leukemia transplant model in male Fischer rats. This in vivo assay measures the effects of chemical treatment on neoplastic progression in transplant recipients. Chemicals were given ad libitum in the drinking water simultaneously with the transplants and continued throughout the study. In all, 20 million leukemic cells were injected s.c. into syngeneic rats, which after 60 days resulted in a 10-fold increase in relative spleen weights, a 100-fold increase in white blood cell counts, and a 50% reduction in red blood cell (RBC) indices and platelet counts. At this interval, ethylene glycol monomethyl ether (2-ME) given at a dose of 2.5 mg/ml in the drinking water completely eliminated all clinical, morphological, and histopathological evidence of leukemia, whereas the same dose of ethylene glycol monoethyl ether (2-EE) reduced these responses by about 50%. Seven of the glycol ethers were ineffective as anti-leukemic agents, including ethylene glycol, the monopropyl, monobutyl, and monophenyl ethylene glycol ethers, diethylene glycol, and the monomethyl and monoethyl diethylene glycol ethers. 2-ME more than doubled the latency period of leukemia expression and extended survival for at least 210 days. A minimal effective dose for a 50% reduction in the leukemic responses was 0.25 mg/ml 2-ME in the drinking water (15 mg/kg body weight), whereas a 10-fold higher dose of 2-EE was required for equivalent antileukemic activity. In addition, the in vitro exposure of a leukemic spleen mononuclear cell culture to 2-ME caused a dose- and time-dependent reduction in the number of leukemia cells after a single exposure to 1-100 microM concentrations, whereas the 2-ME metabolite, 2-methoxyacetic acid, was only half as effective. The two glycol alkyl ethers with demonstrable anti-leukemic activity, 2-ME and 2-EE, also exhibited a favorable efficacy-to-toxicity ratio and should be considered for further development as chemotherapeutic agents.
利用雄性Fischer大鼠的细胞白血病移植模型，对9种乙二醇烷基醚进行了构效关系研究。这种体内试验可测定化学处理对移植受体肿瘤进展的影响。在移植的同时，让大鼠自由饮用含有化学物质的水，并在整个研究过程中持续提供。总共将2000万个白血病细胞皮下注射到同基因大鼠体内，60天后，大鼠脾脏相对重量增加了10倍，白细胞计数增加了100倍，红细胞（RBC）指数和血小板计数减少了50%。在此期间，饮用水中剂量为2.5 mg/ml的乙二醇单甲醚（2-ME）完全消除了白血病的所有临床、形态学和组织病理学证据，而相同剂量的乙二醇单乙醚（2-EE）使这些反应降低了约50%。7种乙二醇醚作为抗白血病药物无效，包括乙二醇、单丙基、单丁基和单苯基乙二醇醚、二乙二醇以及单甲基和单乙基二乙二醇醚。2-ME使白血病表达的潜伏期延长了一倍多，并使生存期延长了至少210天。饮用水中2-ME的最小有效剂量为使白血病反应降低50%时为0.25 mg/ml（体重15 mg/kg），而2-EE需要高10倍的剂量才能产生等效的抗白血病活性。此外，白血病脾脏单核细胞培养物在体外暴露于2-ME后，单次暴露于1-100 microM浓度时，白血病细胞数量会出现剂量和时间依赖性减少，而2-ME的代谢产物2-甲氧基乙酸的效果仅为其一半。两种具有明显抗白血病活性的乙二醇烷基醚2-ME和2-EE也表现出良好的效毒比，应考虑作为化疗药物进一步开发。
