A comparison in rodents of renal and intestinal toxicity of cisplatin and a new water-soluble antitumor platinum complex: N-methyl-iminodiacetato-diaminocyclohexane platinum (II).
A comparison in rodents of renal and intestinal toxicity of cisplatin and a new water-soluble antitumor platinum complex: N-methyl-iminodiacetato-diaminocyclohexane platinum (II).
复制标题
顺铂与新型水溶性抗肿瘤铂络合物：N-甲基-亚氨基二乙酸基-二氨基环己烷铂 (II) 在啮齿类动物中的肾脏和肠道毒性比较。
DOI：
10.1016/0041-008x(86)90250-4
复制
发表时间：
1986
影响因子：
3.8
通讯作者：
Bulger,RE
中科院分区：
文献类型：
--
作者：
Newman,RA;Khokhar,AR;Sunderland,BA;Travis,EL;Bulger,RE
一种新的第三代水溶性铂配合物N-甲基亚氨二乙酸二乙酯-1，2-二氨基环己烷铂(II)(MIDP)被报道对几种小鼠肿瘤模型系统具有显著的抗肿瘤活性。在本研究中，直接比较了MIDP和顺铂(顺铂)的肾和肠毒性。对Fischer 344大鼠分别给予等剂量顺铂或MIDP(6.0 mg/kg和25 mg/kg)后3天和5天的肾脏生理参数的测定表明，顺铂显著降低肾小球滤过率(GFR)，升高血尿素氮(BUN)和血肌酐水平，而MIDP对GFR和BUN水平均无影响，仅轻微升高血肌酐(第5天)。光镜和电子显微镜下的组织病理学分析显示，顺铂治疗的大鼠肾近端肾小管严重坏死，而MIDP未产生可检测到的损害。元素铂含量的测定显示，与顺铂治疗的动物相比，MIDP治疗的大鼠肾脏中滞留的铂更少。通过测定小鼠空肠隐窝细胞再生情况，判断药物对小鼠肠道的损伤程度。顺铂使隐窝存活率降低1log，而即使在超过半数致死剂量的MIDP剂量下，也没有观察到对隐窝细胞的杀伤。我们的数据表明，与顺铂相比，MIDP的肾和肠道毒性要小得多。
A new third-generation water-soluble platinum complex, N-methyliminodiacetato-1,2-diaminocyclohexane platinum (II) (MIDP) has been reported to have remarkable antitumor activity against several murine tumor model systems. In the present study, the renal and intestinal toxicity of MIDP was compared directly with that of cis-diamminedichloroplatinum (cisplatin). Measurement of renal physiologic parameters in Fischer 344 rats 3 and 5 days after receiving equitherapeutic doses of either cisplatin or MIDP (6.0 and 25 mg/kg, respectively) revealed that, whereas cisplatin significantly reduced glomerular filtration rates (GFR) and increased blood urea nitrogen (BUN) and serum creatinine values, MIDP produced no alteration in either GFR or BUN levels and only a slight rise (Day 5) in serum creatinine value. Histopathologic analyses by light and electron microscopy showed severe renal proximal tubular necrosis in cisplatin-treated rats yet no detectable lesions were produced by MIDP. Determination of elemental platinum content revealed that less platinum was retained in the kidneys of MIDP-treated rats than in cisplatin-treated animals. The degree of drug-mediated intestinal injury was determined for each drug by measurement of jejunal crypt cell regeneration in mice. Cisplatin reduced crypt survival by 1 log whereas no killing of crypt cells was seen even at MIDP doses exceeding the median lethal dose. Our data demonstrate that far less renal and intestinal toxicity results from administration of MIDP than from administration of cisplatin.