Cisplatin Mouse Models: Treatment, Toxicity and Translatability

Abstract

Cisplatin is one of the most widely used chemotherapeutic drugs in the treatment of a wide range of pediatric and adult malignances. However, it has various side effects which limit its use. Cisplatin mouse models are widely used in studies investigating cisplatin therapeutic and toxic effects. However, despite numerous promising results, no significant improvement in treatment outcome has been achieved in humans. There are many drawbacks in the currently used cisplatin protocols in mice. In the paper, the most characterized cisplatin protocols are summarized together with weaknesses that need to be improved in future studies, including hydration and supportive care. As demonstrated, mice respond to cisplatin treatment in similar ways to humans. The paper thus aims to illustrate the complexity of cisplatin side effects (nephrotoxicity, gastrointestinal toxicity, neurotoxicity, ototoxicity and myelotoxicity) and the interconnectedness and interdependence of pathomechanisms among tissues and organs in a dose- and time-dependent manner. The paper offers knowledge that can help design future studies more efficiently and interpret study outcomes more critically. If we want to understand molecular mechanisms and find therapeutic agents that would have a potential benefit in clinics, we need to change our approach and start to treat animals as patients and not as tools.

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

“…Moreover, Pd 2 Spm administration did not result in significant variations regarding hematological and biochemical parameters when compared to cisplatin-treated animals which evidenced signs of macrocytic anemia (decrease in red blood cells, hemoglobin and hematocrit together with an increase in mean corpuscular volume). The cisplatin-induced changes in body weight, diarrhea and hematotoxicity were previously described [ 34 , 35 ] and are generally considered as surrogates for the drug’s systemic toxicity. Furthermore, these results support the reduced off-target effects and low toxicity elicited by Pd 2 Spm treatment compared to cisplatin.…”

Liposomal Artificial Red Blood Cell-Based Carbon Monoxide Donor Is a Potent Renoprotectant against Cisplatin-Induced Acute Kidney Injury

“…Although the extent of renal injury was not evaluated due to the insufficient number of surviving mice at the endpoint (on day 14), the amelioration of CDDP-induced nephrotoxicity by CO-HbV pretreatment would, in part, result in minimal impact on body weight and survival. Notably, the CDDP mouse model not only induces nephrotoxicity but also results in other adverse effects, such as gastrointestinal toxicity [36], and the protective roles of CO-HbV in such adverse events may contribute to its overall beneficial effects. It was also examined whether CO-HbV pretreatment led to the successful antitumor activity of CDDP with minimal adverse effects in vivo.…”

Renoprotective Effect of Pediococcus acidilactici GKA4 on Cisplatin-Induced Acute Kidney Injury by Mitigating Inflammation and Oxidative Stress and Regulating the MAPK, AMPK/SIRT1/NF-κB, and PI3K/AKT Pathways

“…For example, cisplatin at a dose of 20 mg/kg caused severe morphological damage in the kidneys and elevated BUN levels already 3 days after a single intraperitoneal injection, resulting in death within 5 days of injection [ 27 ]. Cisplatin at a dose of 40 mg/kg following a single cisplatin injection caused systemic toxicity within 1–2 days and death within 4 days [ 30 ]. Cellular uptake of cisplatin is mediated by transporters such as organic cation transporters (OCTs) and copper transporters (CTRs).…”