Szabó D, Molnár J
Department of Microbiology, Albert Szent-Györgyi Medical University, Szeged, Hungary.
Anticancer Res. 1998 Jul-Aug;18(4C):3039-44.
The effect of three different stereoisomer pairs of CNS (central nervous system) active compounds was studied on the activity of human mdr1 p-glycoprotein. The methotrimeprazine, clopenthixol and butaclamol isomers had an antiproliferative effect (ID50) on the mdr1 expressing cells at 0.250 microgram/ml, while the parental cells were less sensitive having ID50 at 0.37-0.69 microgram/ml. Enantiomers of methotrimeprazine and clopenthixol had similar effectivity on the drug efflux of mdr cells. However, (-)butaclamol was found to inhibit mdr efflux-pump activity much more than the CNS active (+) isomer. Based on these results, tricyclic compounds does not seem to have stereoselectivity in methotrimeprazine and clopenthixol on the mdr reversal effect. In general, both active and inactive members of stereoisomers had a similar effect on the drug accumulation of the mdr cells. Therefore, hypothetically the CNS inactive member of stereoisomer pairs can be used as a resistance modifier without any risk in patients suffering from drug resistant cancer.
研究了三种不同的中枢神经系统（CNS）活性化合物立体异构体对人多药耐药蛋白1（mdr1）P-糖蛋白活性的影响。甲硫哒嗪、氯哌噻吨和布他拉莫异构体对表达mdr1的细胞具有抗增殖作用（半数抑制浓度ID50），浓度为0.250微克/毫升，而亲代细胞敏感性较低，ID50为0.37 - 0.69微克/毫升。甲硫哒嗪和氯哌噻吨的对映体对mdr细胞的药物外排具有相似的效果。然而，发现（-）布他拉莫比具有中枢神经系统活性的（+）异构体更能抑制mdr外排泵活性。基于这些结果，三环类化合物在甲硫哒嗪和氯哌噻吨对mdr逆转作用方面似乎没有立体选择性。一般来说，立体异构体的活性和非活性成员对mdr细胞的药物蓄积具有相似的作用。因此，假设立体异构体对中的中枢神经系统非活性成员可作为耐药修饰剂，用于患有耐药性癌症的患者而无任何风险。
