Nygaard M E, Pettersen E O, Dornish J M, Undheim K, Oftebro R
Department of Tissue Culture, Norwegian Radium Hospital, Montebello, Oslo.
Invest New Drugs. 1987;5(3):259-66. doi: 10.1007/BF00175296.
The effect of the two closely related drugs, the sulfone 2-(2-thenyl)sulfonyl-5-bromopyrimidine (NY 4137), and the sulfoxide 2-(2-thenyl)sulfinyl-5-bromopyrimidine (NY 4138), a sulfoxide, on the survival of cells of the human line NHIK 3025 was investigated. Cell survival was measured as the ability of single cells to form macroscopic colonies. Two-hour treatment with 0.012 mM NY 4137 resulted in 50% inactivation. The drug concentration of NY 4138 had to be adjusted about 10 times higher than that of NY 4137 for treatment periods of 2 or 24 h to obtain similar surviving fraction after treatment of asynchronous cells. Treatment of synchronized NHIK 3025 cells with NY 4137 showed that survival varied little with cell age. Following treatment with NY 4138, however, cells were particularly sensitive in G2 and in mitosis. As the survival curves for both drugs display a plateau region, where increasing the drug dose has little or no effect on cell inactivation, the presence of resistant subpopulations of cells is considered. High-performance liquid chromatography of drug solutions in cell culture medium showed that both NY 4137 and NY 4138 bound to, or were metabolized by, medium and/or cell components. The concentration of NY 4137 in cell culture medium, however, was reduced at a higher rate than NY 4138. The half-life of NY 4137 was on the order of 5 h, while the half-life of NY 4138 was over 24 h. These observations correlate well with the relative chemical reactivities for these drugs in nucleophilic displacement reactions.
研究了两种密切相关的药物，砜类化合物2-(2-噻吩基)磺酰基-5-溴嘧啶(NY 4137)和亚砜类化合物2-(2-噻吩基)亚磺酰基-5-溴嘧啶(NY 4138)对人源NHIK 3025细胞系细胞存活的影响。细胞存活以单细胞形成肉眼可见集落的能力来衡量。用0.012 mM NY 4137处理两小时导致50%的细胞失活。对于2小时或24小时的处理期，NY 4138的药物浓度必须调整为比NY 4137高约10倍，才能在处理非同步细胞后获得相似的存活分数。用NY 4137处理同步化的NHIK 3025细胞表明，细胞存活率随细胞年龄变化不大。然而，用NY 4138处理后，细胞在G2期和有丝分裂期特别敏感。由于两种药物的存活曲线都显示出一个平台区，在该区域增加药物剂量对细胞失活几乎没有影响，因此考虑存在抗性细胞亚群。对细胞培养基中药物溶液进行高效液相色谱分析表明，NY 4137和NY 4138都与培养基和/或细胞成分结合或被其代谢。然而，细胞培养基中NY 4137的浓度降低速率比NY 4138高。NY 4137的半衰期约为5小时，而NY 4138的半衰期超过24小时。这些观察结果与这些药物在亲核取代反应中的相对化学反应活性密切相关。
