A low-dose pemetrexed-cisplatin combination regimen induces significant nephrotoxicity in mice.

IF 2.2 4区 医学 Q2 UROLOGY & NEPHROLOGY
Samson A Iwhiwhu, Ravi Kumar, Abdul H Khan, Jeremiah M Afolabi, Jada D Williams, Julia E de la Cruz, Adebowale Adebiyi
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引用次数: 0

Abstract

Background: Pemetrexed is combined with cisplatin to treat cancer. Whether pemetrexed-cisplatin combination chemotherapy exacerbates cisplatin nephrotoxicity is unclear. Here, we investigated kidney injury in mice administered a non-lethal low-dose regimen of pemetrexed or cisplatin alone and compared it with a pemetrexed-cisplatin combination.

Methods: Mice were randomly divided into four groups and administered intraperitoneally the experimental drugs solubilized in captisol (sulfobutylether β-cyclodextrin). Group 1 received captisol, Group 2 pemetrexed (10 mg/kg), Group 3 cisplatin (1 mg/kg), and Group 4 pemetrexed (10 mg/kg) plus cisplatin (1 mg/kg). The mice were treated every other day for two weeks, three times per week. Glomerular filtration rate (GFR) was determined on the third day after the last treatment, followed by a necropsy.

Results: Whereas the relative kidney weight was comparable in the control vs. pemetrexed or cisplatin alone group, it was significantly increased in the combination group. Mice treated with cisplatin and pemetrexed-cisplatin combination exhibited reduced GFR. The pemetrexed-cisplatin combination caused significant increases in the plasma or urinary levels of kidney injury biomarkers, renal lipid peroxidation, and nitrosative stress compared with pemetrexed or cisplatin alone. Histopathology revealed that pemetrexed or cisplatin alone had minimal effects on the kidneys. By contrast, the pemetrexed-cisplatin combination caused tubular degeneration, dilatation, and granular casts. Live-cell imaging showed that the pemetrexed-cisplatin combination caused more severe apoptosis of primary renal epithelial cells than individual concentrations.

Conclusions: These findings suggest that combining pemetrexed and cisplatin causes oxidative kidney damage at individual doses that do not cause significant nephrotoxicity. Hence, the renal function of patients undergoing treatment with the pemetrexed-cisplatin combination needs extensive monitoring.

低剂量培美曲塞-顺铂联合疗法会对小鼠产生明显的肾毒性。
背景:培美曲塞与顺铂联合治疗癌症。培美曲塞与顺铂联合化疗是否会加重顺铂的肾毒性尚不清楚。在此,我们研究了小鼠肾损伤的情况,小鼠单独接受非致死性低剂量培美曲塞或顺铂治疗,并与培美曲塞-顺铂联合治疗进行比较:将小鼠随机分为四组,腹腔注射溶解在卡替洛尔(磺丁醚 β-环糊精)中的实验药物。第 1 组接受卡替洛尔,第 2 组接受培美曲塞(10 毫克/千克),第 3 组接受顺铂(1 毫克/千克),第 4 组接受培美曲塞(10 毫克/千克)加顺铂(1 毫克/千克)。小鼠每隔一天接受一次治疗,连续两周,每周三次。在最后一次治疗后的第三天测定肾小球滤过率(GFR),然后进行尸体解剖:结果:对照组与培美曲塞或顺铂单药组的肾脏相对重量相当,而联合治疗组的肾脏相对重量明显增加。接受顺铂和培美曲塞-顺铂联合治疗的小鼠表现出肾小球滤过率降低。与培美曲塞或顺铂单药相比,培美曲塞-顺铂联合用药会导致血浆或尿液中肾损伤生物标志物、肾脂质过氧化物和亚硝基应激水平明显升高。组织病理学显示,单用培美曲塞或顺铂对肾脏的影响微乎其微。相比之下,培美曲塞-顺铂联合疗法会导致肾小管变性、扩张和颗粒状结节。活细胞成像显示,与单个浓度相比,培美曲塞-顺铂联合用药导致的原发性肾上皮细胞凋亡更为严重:这些研究结果表明,培美曲塞和顺铂联合使用会造成氧化性肾损伤,但单个剂量不会引起明显的肾毒性。因此,需要对接受培美曲塞-顺铂联合治疗的患者的肾功能进行广泛监测。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Nephrology
BMC Nephrology UROLOGY & NEPHROLOGY-
CiteScore
4.30
自引率
0.00%
发文量
375
审稿时长
3-8 weeks
期刊介绍: BMC Nephrology is an open access journal publishing original peer-reviewed research articles in all aspects of the prevention, diagnosis and management of kidney and associated disorders, as well as related molecular genetics, pathophysiology, and epidemiology.
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