Synergistic bone marrow toxicity of pyrimethamine and zidovudine in murine in vivo and in vitro models: mechanism of toxicity.
Synergistic bone marrow toxicity of pyrimethamine and zidovudine in murine in vivo and in vitro models: mechanism of toxicity.
复制标题
乙胺嘧啶和齐多夫定在小鼠体内和体外模型中的协同骨髓毒性：毒性机制。
DOI：
10.1006/taap.2002.9397
复制
发表时间：
2002
影响因子：
3.8
通讯作者：
MacGregor,JamesT
中科院分区：
文献类型：
--
作者：
Freund,YvonneR;Dabbs,Jack;Creek,MoireR;Phillips,SandraJ;Tyson,CharlesA;MacGregor,JamesT
乙胺嘧啶（Pyr）通常用于治疗艾滋病患者的弓形虫脑炎；然而，在两项临床研究中，当 Pyr 与齐多夫定 (ZDV) 合用时，观察到死亡人数增加。选择 BALB/c 小鼠作为模型来研究这些药物联合用药产生意外毒性的机制。每日口服 60 mg/kg Pyr 和 240 mg/kg ZDV，30 天后致死率达到 100%。当这些药物在同一时期单独给药时，这些剂量水平没有产生影响。 Pyr 和 ZDV 联合用药导致大细胞性贫血和白细胞减少，并协同减少淋巴细胞和中性粒细胞数量。为了在细胞水平上研究这种血液毒性的机制，采用了小鼠骨髓集落形成单位（mCFU）测定。 ZDV 与不同浓度的 Pyr 组合可导致红细胞和粒细胞巨噬细胞前体细胞（mCFU-E 和 mCFU-GM）数量协同减少。 mCFU-GM 前体似乎比红细胞前体对 Pyr 和 ZDV 的组合更敏感。在 mCFU-GM 测定中，当 Pyr 浓度增加时，14 C-ZDV 掺入细胞 DNA 的情况以剂量依赖性方式增加。这表明Pyr对二氢叶酸还原酶的抑制以及伴随的dTTP合成的抑制使得ZDV优先掺入DNA中，导致链断裂和细胞死亡。在分析人类GM培养物时也观察到14C-ZDV掺入，但是掺入较少并且需要更高浓度的Pyr。
Pyrimethamine (Pyr) is commonly used for treatment of toxoplasmic encephalitis in AIDS patients; however, in two clinical studies, an increased number of deaths were observed when Pyr was coadministered with zidovudine (ZDV). The BALB/c mouse was chosen as a model to study the mechanism underlying the unexpected toxicity from coadministration of these drugs. Daily administration by oral gavage of 60 mg/kg Pyr and 240 mg/kg ZDV resulted in 100% lethality after 30 days. These dose levels produced no effect when the drugs were given individually for the same period. Administration of combinations of Pyr and ZDV resulted in macrocytic anemia and leukopenia with synergistic decreases in lymphocyte and neutrophil numbers. To examine the mechanism of this hematotoxicity at the cellular level, mouse bone marrow colony-forming unit (mCFU) assays were employed. A combination of ZDV with various concentrations of Pyr resulted in synergistic decreases in numbers of erythroid and granulocyte-macrophage precursors (mCFU–E and mCFU–GM). mCFU–GM precursors appeared more sensitive than erythroid precursors to combinations of Pyr and ZDV. Incorporation of14C-ZDV into cellular DNA was increased in a dose-dependent manner in the presence of increasing concentrations of Pyr in the mCFU–GM assay. This suggested that inhibition of dihydrofolate reductase by Pyr and accompanying inhibition of dTTP synthesis allows preferential incorporation of ZDV into DNA, with resulting strand breakage and cell death.14C-ZDV incorporation was also observed when human GM cultures were analyzed, however, incorporation was less and required higher concentrations of Pyr.