Species specific differences in the toxicity of mithramycin, chromomycin A3, and olivomycin towards cultured mammalian cells
Species specific differences in the toxicity of mithramycin, chromomycin A3, and olivomycin towards cultured mammalian cells
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光神霉素、铬霉素 A3 和橄榄霉素对培养哺乳动物细胞的毒性的物种特异性差异
DOI：
10.1002/jcp.1041130104
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发表时间：
1982
影响因子：
5.6
通讯作者：
Radhey S. Gupta
中科院分区：
文献类型：
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作者：
Radhey S. Gupta
三种结构相关的抗癌药物，米霉素、色霉素A3和橄榄霉素，对不同物种（人类、中国仓鼠、叙利亚仓鼠和小鼠）的培养细胞的毒性显示出巨大的意想不到的差异（高达1000倍以上）。在所检测的细胞类型中，人类细胞（二倍体成纤维细胞株和HeLa细胞）对所有这些药物最敏感，其次是叙利亚仓鼠肾细胞（bhk21）。小鼠（LMTK−细胞）和中国仓鼠（CHO）细胞对这些药物的敏感性存在有趣的差异。例如，虽然小鼠细胞比CHO细胞对米霉素更耐药，但对色霉素A3和橄榄霉素的敏感性模式却相反。从人类、小鼠和中国仓鼠细胞中提取的细胞提取物中，RNA合成（这些药物的细胞靶点）对米霉素和色霉素A3的敏感性相同，表明对这些药物的毒性的物种特异性差异是在这些化合物的细胞进入水平上。基于这些糖苷类抗生素的结构及其毒性模式，我们认为这些药物的细胞内转运涉及这些化合物上的糖残基与某些类型的细胞表面受体之间的特异性相互作用，这些受体在不同的细胞类型中是不同的。讨论了这些结果对毒性研究的一些意义。
Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, showed large unexpected differences (up to more than 1000 fold) in their toxicity towards cultured cells from various species (human, Chinese hamster, Syrian hamster, and mouse). Among the cell types examined, human cells (both a diploid fibroblast cell strain and HeLa cells) were maximally sensitive to all these drugs, followed by the Syrian hamster kidney cells (BHK 21). The mouse (LMTK− cells) and Chinese hamster (CHO) cells, which were more resistant, showed interesting differences in their sensitivity towards these drugs. For example, whereas the mouse cells were more resistant to mithramycin than CHO cells, the sensitivity pattern was reversed for both chromomycin A3 and olivomycin. In cell extracts derived from human, mouse, and Chinese hamster cells RNA synthesis, which is the cellular target of these drugs, showed identical sensitivity to both mithramycin and chromomycin A3, indicating that the species specific differences in the toxicity to these drugs are at the level of cellular entry of these compounds. Based on the structures of these glycosidic antibiotics and their patterns of toxicity, it is suggested that the intracellular transport of these drugs involves specific interactions between the sugar residues on these compounds and some type of cell surface receptor(s), which differ among different cell types. Some implications of these results for toxicity studies are discussed.