Abstract
Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg/kg cisplatin, where significant weight loss >10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.
Highlights
Hearing loss (HL) is the most common neurosensory deficit in humans, with over 5% of the worldwide population affected (WHO, March 2020 report), recognized as a major and growing socioeconomic burden leading to cognitive decline, depression, and social isolation (Panza et al, 2015; Rutherford et al, 2018).Cisplatin is a widely used lifesaving chemotherapy used against different types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas (Dasari and Tchounwou, 2014)
We observed a correlation between the amount of Pt retained in the cochlea and the volume of cisplatin delivered in the tympanic bulla (r2 = 0.7517)
Animals receiving a volume of cisplatin
Summary
Cisplatin (cis-diaminedichloroplatinum) is a widely used lifesaving chemotherapy used against different types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas (Dasari and Tchounwou, 2014). The antitumor effect of cisplatin is largely unspecific, leading to important systemic adverse effects including nephrotoxicity (Miller et al, 2010), neurotoxicity, myelosuppression, and ototoxicity (Dasari and Tchounwou, 2014). The incidence and severity of cisplatin-induced ototoxicity in humans vary widely in the literature, ranging from 12.5 to 100% in children and 26–100% in adults, depending on the HL criteria used for analysis (Landier, 2016). In a retrospective analysis of a large collection of 401 adults treated with cisplatin in Geneva’s University Hospital, significant HL was found in 20% of cases, among whom 60% experienced tinnitus
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