Hacker M, Roberts D W
Cancer Res. 1975 Jul;35(7):1756-60.
The development of toxicity to 4'-demethylepipodophyllotoxin-9-(4,6,-O-thenylidene-beta-glucopyranoside) an epipodophyllotoxin with oncolytic activity, was characterized in mice treated three times at 3-day intervals with 10 mg of drug i.p. per kg of body weight. Changes in organ function and general metabolism were determined by measuring 18 constituents of blood for up to 10 weeks after drug administration. The results indicate three distinct phases of toxicity to 4'-demethylepipodophyllotoxin 9-(4,6-O-2-thenylidene-beta-glucopyranoside). Acute toxicity developed within the first 10 days and was expressed by a depressed hematocrit and elevated plasma levels of glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lactic dehydrogenase, amylase, lipase, and uric acid. By 4 weeks, levels ahd returned to normal. The acute phase was followed by a chronic phase, which was characterized by progressive decreases in plasma levels of glucose, cholesterol, albumin, and total protein. Finally, about 7 weeks after treatment, a terminal phase indicated by correlated increases in glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lactic dehydrogenase, and blood urea nitrogen became apparent. Plasma levels of creatine phosphokinase, calcium, inorganic phosphate, total bilirubin, ketones, and alkaline phosphatase did not change. Although the pancreas liver and marrow were all affected during acute toxicity, boserved changes in blood components during the chronic and terminal phases correlate best with continued hepatotoxicity. The present evidence on delayed toxicity to 4'-demethylepipodophyllotoxin 9-(4,6-o-2-thenylidene-beta-D-glucopyranoside) is most compatible with irreversible hepatotoxocity which leads to metabolic deficiencies and terminates in death of mice.
对具有溶瘤活性的表鬼臼毒素4'-去甲基表鬼臼毒素-9-(4,6-O-亚苄基-β-D-吡喃葡萄糖苷)的毒性发展情况，在以每千克体重10毫克药物腹腔注射、每隔3天给药3次的小鼠身上进行了表征。给药后长达10周内，通过检测血液中的18种成分来确定器官功能和一般代谢的变化。结果表明，对4'-去甲基表鬼臼毒素-9-(4,6-O-亚苄基-β-D-吡喃葡萄糖苷)的毒性有三个不同阶段。急性毒性在最初10天内出现，表现为血细胞比容降低以及血浆中谷氨酸丙酮酸转氨酶、谷氨酸草酰乙酸转氨酶、乳酸脱氢酶、淀粉酶、脂肪酶和尿酸水平升高。到4周时，这些水平已恢复正常。急性期之后是慢性期，其特征是血浆中葡萄糖、胆固醇、白蛋白和总蛋白水平逐渐下降。最后，在治疗约7周后，出现了一个终末期，表现为谷氨酸丙酮酸转氨酶、谷氨酸草酰乙酸转氨酶、乳酸脱氢酶和血尿素氮相关升高。血浆中肌酸磷酸激酶、钙、无机磷、总胆红素、酮体和碱性磷酸酶水平没有变化。虽然在急性毒性期间胰腺、肝脏和骨髓均受到影响，但在慢性期和终末期观察到的血液成分变化与持续的肝毒性最为相关。目前关于4'-去甲基表鬼臼毒素-9-(4,6-O-亚苄基-β-D-吡喃葡萄糖苷)延迟毒性的证据最符合不可逆肝毒性，这种肝毒性导致代谢缺陷并最终导致小鼠死亡。
