Hładoń B, Sloderbach A, Laskowska H
Department of Pharmacology, Karol Marcinkowski University of Medical Sciences, Poznań, Poland.
Pol J Pharmacol. 1997 Mar-Jun;49(2-3):127-36.
Nine investigated chlorobromine-, bromine-, and dibromine-ifosfamide analogues including 3 racemates and 6 enantiomers, caused about 10-fold increase in in vitro cytotoxic activity, similar to reference standards ifosfamide and cyclophosphamide in HeLa (KB) human tumor cell culture systems with the addition of rat liver microsomal preparations (ED50 = 0.11 - 0.27 x 10(-3) mole/l) as compared to microsomally non induced samples. The chlorobromine-analogues (ED50 = 0.11 - 0.20 x 10(-3) mole/l) demonstrated the highest cytotoxicity in comparison with bromine-, or dibromine-analogues (SAR). Their levorotatory (-)-(S)- enantiomers (ED50 = 0.11 : 0.21 : 0.24 x 10(-3) mole/l) appear to be more active than their dextrorotatory (+)-(R)-antipodes (ED50 = 0.20 : 0.26 : 0.27 x 10(-3) mole/l, respectively) (ESAR). The stereodifferentiated enhancement of their in vitro cytotoxicity, correlated with the decreasing of in vivo L1210 antileukemic effect following phenobarbital metabolic induction in terms of a whole--strong antitumor activity, indicate that their cytostatic activity depends enantioselectively on the mixed function oxidases-system activity, and presumably on the efficacy of the rate of drug metabolic transformation to their cytostatically active metabolites/intermediates.
九种被研究的氯溴、溴和二溴异环磷酰胺类似物，包括3种外消旋体和6种对映体，在体外细胞毒性活性方面引起了约10倍的增加，在添加大鼠肝微粒体制剂的HeLa（KB）人肿瘤细胞培养系统中，与参考标准异环磷酰胺和环磷酰胺相似（ED50 = 0.11 - 0.27 x 10(-3)摩尔/升），相比微粒体未诱导的样品。氯溴类似物（ED50 = 0.11 - 0.20 x 10(-3)摩尔/升）与溴或二溴类似物相比显示出最高的细胞毒性（构效关系）。它们的左旋（-）-（S）-对映体（ED50 = 0.11 : 0.21 : 0.24 x 10(-3)摩尔/升）似乎比它们的右旋（+）-（R）-对映体（分别为ED50 = 0.20 : 0.26 : 0.27 x 10(-3)摩尔/升）更具活性（对映体构效关系）。它们体外细胞毒性的立体选择性增强，与苯巴比妥代谢诱导后体内L1210抗白血病作用的降低相关，就整体强大的抗肿瘤活性而言，表明它们的细胞生长抑制活性对映选择性地取决于混合功能氧化酶系统的活性，并且大概取决于药物代谢转化为其细胞生长抑制活性代谢物/中间体的速率的功效。
