Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri Columbia, MO, 65211, USA.
BMC Nephrol. 2024 Oct 21;25(1):370. doi: 10.1186/s12882-024-03822-5.
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.
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.
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.
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.
培美曲塞与顺铂联合用于治疗癌症。培美曲塞-顺铂联合化疗是否会加重顺铂肾毒性尚不清楚。在此，我们研究了非致死性低剂量培美曲塞或顺铂单药治疗以及培美曲塞-顺铂联合治疗的小鼠的肾损伤情况。
将小鼠随机分为四组，腹腔内给予溶于captisol（磺丁基醚-β-环糊精）的实验药物。第 1 组给予 captisol，第 2 组给予培美曲塞（10mg/kg），第 3 组给予顺铂（1mg/kg），第 4 组给予培美曲塞（10mg/kg）加顺铂（1mg/kg）。小鼠每两天治疗一次，每周三次，共两周。最后一次治疗后第三天测定肾小球滤过率（GFR），然后进行尸检。
与培美曲塞或顺铂单药组相比，对照组的相对肾脏重量无差异，但联合组明显增加。顺铂和培美曲塞-顺铂联合组的 GFR 降低。与培美曲塞或顺铂单药组相比，培美曲塞-顺铂联合组的肾损伤生物标志物、肾脂质过氧化和硝化应激的血浆或尿液水平显著升高。组织病理学显示，培美曲塞或顺铂单药对肾脏影响较小。相比之下，培美曲塞-顺铂联合组导致肾小管变性、扩张和颗粒状铸型。活细胞成像显示，培美曲塞-顺铂联合组引起的原代肾上皮细胞凋亡比单个浓度更严重。
这些发现表明，培美曲塞和顺铂联合使用会导致单独剂量不引起明显肾毒性的情况下发生氧化肾损伤。因此，接受培美曲塞-顺铂联合治疗的患者需要对肾功能进行广泛监测。
