Inhibition of Trypanosoma cruzi growth in mammalian cells by purine and pyrimidine analogs
Inhibition of Trypanosoma cruzi growth in mammalian cells by purine and pyrimidine analogs
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DOI：
10.1128/aac.40.11.2455
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发表时间：
1996-11-01
影响因子：
4.9
通讯作者：
Aoki, T
中科院分区：
文献类型：
--
作者：
NakajimaShimada, J;Hirota, Y;Aoki, T
克氏锥虫（Trypanosomacruzi）是引起南美锥虫病的病原体，在哺乳动物体内具有两个不同的发育阶段，即无鞭毛体和锥鞭毛体。Cruzi，其中定量地确定寄生虫生长的时间过程。我们采用该系统筛选抗锥虫的克氏锥虫药物，这些药物理想地被证明对锥虫有效而对宿主细胞没有毒性。在所测试的嘌呤类似物中，别嘌呤醇以剂量依赖的方式显著抑制无鞭毛体的生长，而对锥虫无致死作用，3 '-脱氧肌苷和3'-脱氧腺苷也抑制锥虫。宿主细胞内的克氏生长，引起50%生长抑制的浓度分别为10和5 μ M，与别嘌呤醇引起50%生长抑制的浓度3 μ M相反，在检测的嘧啶类似物中，3 ′-叠氮基-3 ′-脱氧胸苷（齐多夫定）在低至1 μ M的浓度下显著降低寄生虫的生长。抗人类免疫缺陷病毒药物2 ′，3 ′-双脱氧肌苷和2 ′，3 ′-双脱氧腺苷可抑制无鞭毛体的生长，而2 ′，3 ′-双脱氧胞苷和2 ′，3 ′-双脱氧尿苷则无抑制作用。克鲁兹增殖这些结果表明，我们的培养系统是有用的，作为一个初步筛选的候选化合物对T。Cruzi基于两个标准，即寄生虫的细胞内复制和宿主细胞感染率。
Trypanosoma cruzi, the causative agent of Chagas' disease, exhibits two different developmental stages in mammals, the amastigote, an intracellular form that proliferates in the cytoplasm of host cells, and the trypomastigote, an extracellular form that circulates in the bloodstream, We have already established an in vitro culture system using mammalian host cells (HeLa) infected with T. cruzi in which the time course of parasite growth is determined quantitatively. We adopted this system for the screening of anti-T, cruzi agents that would ideally prove to be effective against trypanosomes with no toxicity to the host cell, Of the purine analogs tested, allopurinol markedly inhibited the growth of amastigotes in a dose-dependent manner, with no lethal effect on trypomastigotes, 3'-Deoxyinosine and 3'-deoxyadenosine also suppressed T. cruzi growth inside the host cell, with the concentrations causing 50% growth inhibition being 10 and 5 mu M, respectively, in contrast to a concentration causing 50% growth inhibition of 3 mu M for allopurinol, among the pyrimidine analogs examined, 3'-azido-3'-deoxythymidine (zidovudine) significantly reduced the growth of the parasite at concentrations as low as 1 mu M. The anti-human immunodeficiency virus agents 2',3'-dideoxyinosine and 2',3'-dideoxyadenosine caused a decrease in amastigote growth, while 2',3'-dideoxycytidine and 2',3'dideoxyuridine had no inhibitory effect, When Swiss 3T3 fibroblasts were used as host cells, allopurinol, 3'-deoxyinosine, 3'-deoxyadenosine, and 3'-azid-3'-deoxythymidine also markedly inhibited T. cruzi proliferation. These results indicate that our culture system is useful as a primary screening method for candidate compounds against T. cruzi on the basis of two criteria, namely, intracellular replication by the parasite and host-cell infection rate.