Differences in the toxicity and metabolism of the 2-nitroimidazole misonidazole (Ro-07-0582) in HeLa and Chinese hamster ovary cells.
Differences in the toxicity and metabolism of the 2-nitroimidazole misonidazole (Ro-07-0582) in HeLa and Chinese hamster ovary cells.
复制标题
2-硝基咪唑米索硝唑 (Ro-07-0582) 在 HeLa 和中国仓鼠卵巢细胞中的毒性和代谢差异。
作者：
Y. Taylor;A. Rauth
摘要2-硝基咪唑米索硝唑（Ro-07-0582）是一种正在进行临床研究的乏氧细胞放射增敏剂。除了其放射增敏能力外，与需氧细胞相比，它对缺氧的毒性增加。人HeLa细胞对米索硝唑的敏感性比中国仓鼠卵巢细胞高2至3倍，这是因为在5 mm药物中缺氧孵育后，将存活率降低至0.1%所需的时间。使用[ 14 C]米索硝唑研究了这种敏感性差异的基础。与需氧细胞中观察到的相比，低氧细胞中的放射性积累增加，需氧细胞与外部药物水平保持平衡。在5 mm标记药物的存在下，缺氧HeLa细胞以缺氧中国仓鼠卵巢细胞的2至3倍的速率积累放射性。这种积累已被测量为药物浓度和氧气浓度的函数。在1%氧气下，两种细胞系的放射性累积速率均大于在研究的最低氧张力下观察到的最大速率的一半，观察到O -去甲基化衍生物。这些结果表明，HeLa细胞和中国仓鼠卵巢细胞对米索硝唑的敏感性差异是由于它们代谢药物的速率不同。
Abstract The 2-nitroimidazole misonidazole (Ro-07-0582) is a hypoxic cell radiosensitizer currently undergoing clinical investigation. In addition to its radiosensitizing abilities, it shows an increased toxicity toward hypoxic compared to aerobic cells. Human HeLa cells are 2 to 3 times more sensitive to misonidazole in terms of the time required to reduce survival to 0.1% after hypoxic incubations in 5 mm drug than are Chinese hamster ovary cells. The basis of this difference in sensitivity was investigated with the use of [ 14 C]misonidazole. There is an increased accumulation of radioactivity in hypoxic cells over that seen in aerobic cells that remain in equilibrium with external drug levels. In the presence of 5 mm labeled drug, hypoxic HeLa cells accumulate radioactivity at 2 to 3 times the rate of hypoxic Chinese hamster ovary cells. This accumulation has been measured as a function of drug concentration and oxygen concentration. At 1% oxygen both cell lines accumulate radioactivity at greater than one-half the maximum rate seen at the very lowest oxygen tensions studied, O -demethylation derivative are seen. These results suggest that differences in the sensitivity of HeLa and Chinese hamster ovary cells to misonidazole are due to differences in the rate at which they metabolize the drug.