Matsumoto T, Endoh K, Akamatsu K, Kamisango K, Mitsui H, Koizumi K, Morikawa K, Koizumi M, Matsuno T
Exploratory Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan.
Br J Cancer. 1991 Jul;64(1):41-6. doi: 10.1038/bjc.1991.236.
New platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R) and its enantiomeric isomer, (+)-(S)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114S), were compared in their antitumour effects and nephrotoxicity-inducing activities. Both compounds were effective against the murine tumours L1210 and Colon 26 by i.p. injection of 20-100 mg kg-1. While DWA2114S showed marked increases in blood urea nitrogen (BUN) and urinary protein and sugar in BDF1 mice treated i.p. at the maximum tolerated dose, DWA2114R showed no increases in these parameters. To clarify the difference of nephrotoxicity between the isomers, tissue distribution was examined. Renal Pt concentration in DWA2114S-treated mice was more than 5-fold higher compared with that in DWA2114R-treated mice 2h after i.p. injection of 80 mg kg-1. However, there were no such marked differences in the lung, liver, heart, spleen and plasma. The low content of Pt in the kidneys of DWA2114R-treated mice could explain its lower nephrotoxicity. The in vitro experiments for uptake of the drugs into the cultured normal rat kidney cells and fresh splenocytes revealed that the Pt amount in the cells treated with DWA2114S, especially in the kidney cells, was much higher than DWA2114R.
对新型铂配合物（-）-（R）-2-氨甲基吡咯烷（1,1-环丁烷二羧酸根）铂（II）一水合物（DWA2114R）及其对映体异构体（+）-（S）-2-氨甲基吡咯烷（1,1-环丁烷二羧酸根）铂（II）一水合物（DWA2114S）的抗肿瘤作用和肾毒性诱导活性进行了比较。通过腹腔注射20-100mg/kg，两种化合物对小鼠肿瘤L1210和结肠癌26均有效。虽然在以最大耐受剂量腹腔注射处理的BDF1小鼠中，DWA2114S的血尿素氮（BUN）、尿蛋白和尿糖显著增加，但DWA2114R的这些参数没有增加。为了阐明异构体之间肾毒性的差异，研究了组织分布。腹腔注射80mg/kg后2小时，DWA2114S处理的小鼠肾脏中的铂浓度比DWA2114R处理的小鼠高5倍以上。然而，在肺、肝、心、脾和血浆中没有如此明显的差异。DWA2114R处理的小鼠肾脏中铂含量较低可以解释其较低的肾毒性。对药物进入培养的正常大鼠肾细胞和新鲜脾细胞的体外摄取实验表明，DWA2114S处理的细胞，尤其是肾细胞中的铂含量远高于DWA2114R。
