A low-dose pemetrexed-cisplatin combination regimen induces significant nephrotoxicity in mice compared with pemetrexed or cisplatin alone

Pemetrexed is a cytostatic agent used to treat solid tumors and autoimmune diseases. Pemetrexed exerts its antineoplastic activity by multitargeted disruption of folate-dependent processes that mediate cell replication. Pemetrexed is now combined with cisplatin to treat non-small cell lung cancer and malignant mesothelioma. Cisplatin nephrotoxicity is well-established. Recent evidence in humans suggests that pemetrexed monotherapy can cause kidney injury. However, the mechanisms of pemetrexed-induced kidney injury remain unclear. Whether pemetrexed-cisplatin combination chemotherapy exacerbates nephrotoxicity is also unknown. In this study, we investigated acute kidney injury (AKI) in mice administered a low-dose regimen of pemetrexed or cisplatin alone and compared it with a pemetrexed-cisplatin combination. C57BL/6J (8-10 weeks old) male mice were randomly divided into four groups and administered (intraperitoneally) the experimental drugs solubilized in Captisol (sulfobutylether-b-cyclodextrin). Group 1 received Captisol (excipient control), 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. Transdermal glomerular filtration (GFR) measurement was performed on the third day after the last treatment, followed by a necropsy. Whereas body weight changes and kidney-to-body weight ratio were comparable in the control vs. pemetrexed or cisplatin alone group, these indices were significantly increased in the pemetrexed-cisplatin combination group. There was a relative decrease in the GFR of mice treated with pemetrexed or cisplatin alone and in the pemetrexed-cisplatin combination. However, only mice treated with cisplatin and pemetrexed-cisplatin combination showed a significant reduction in GFR. There were trends of increases in the plasma or urinary levels of AKI biomarkers, including blood, urea nitrogen (BUN), creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and cystatin C in control vs. pemetrexed or cisplatin alone. Renal lipid peroxidation and DNA damage were comparable in control vs. pemetrexed or cisplatin alone. However, the mice administered with a combination of pemetrexed and cisplatin showed amplified lipid peroxidation, proteinuria, and AKI. These findings indicate that combining pemetrexed and cisplatin promotes considerable kidney damage at individual doses that do not cause significant nephrotoxicity. Hence, patients treated with pemetrexed-cisplatin combination chemotherapy should be monitored closely for AKI. Disclosure of Funding: NIH: R01 HL151735-01. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.