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Cell viability analysis by MTS assay at different time points (3 h, 24 h, 48 h, and 72 h) after treatment with 5 Gy gamma radiation and 0.5 μg/ml cisplatin (CDDP). After co-treatment with radiation and CDDP, cell viability was significantly reduced at 72 h. The data shown are the most representative of 3 separate experiments.
Source publication
Objective. Combined cisplatin (CDDP) and radiotherapy is increasingly being used to treat advanced head and neck cancers. As both CDDP and radiation can cause hearing loss, it is important to have a better understanding of the cellular and molecular ototoxic mechanisms involved in combined therapy. Procedure.
The effects of CDDP, radiation, and co...
Context in source publication
Context 1
... viability analysis by MTS assay at different time points revealed that although CPPD and radiation each exerted a negative effect on cell viability, treatment when combined appeared to have a greater effect. These effects were observed at 48 hrs after treatment and became even more marked at 72 hrs after treatment (Figure 1). ...Citations
... Several miRNAs confer cell's resistance ot CDDP, and these miRNAs are usually delivered by extracellular vesicles or exosomes [36] . One significant mechanism is downregulating pro-apoptotic mRNAs and intracellular signaling pathways [37] . Therefore, miRNAs transferred by hUCMSC-EVs may help GCs survive CDDP treatment via degrading pro-apoptotic mRNA or reducing their translation activity. ...
... Regarding radiotherapy, although most studies indicate a strong relationship of ototoxicity to head and neck tumors [32][33][34] , simultaneous administration to chemotherapeutic agents can potentiate the effects of cell apoptosis in the cochlea 35 . Previous investigations that have verified the effect of treatment with chemotherapy and radiotherapy on breast, cervical and uterine neoplasms in the auditory system report the presence of hearing loss in both treatments 23 . ...
Objective: To analyze the occurrence of tinnitus and peripheral sensory neuropathy in women during breast cancer chemotherapy. Methods: This is a retrospective analytical study with a quantitative approach, performed in medical records of an oncology outpatient service between February 2014 and February 2015, using the toxicities scores of Common Terminology Criteria for Adverse Events (CTCAE). Results: Considering 181 patients with breast cancer who met the inclusion criteria, 49.2% reported tinnitus at some point of the treatment, while 65.1% peripheral sensory neuropathy. In both conditions, the predominant severity score was grade 1, with frequencies of 23.8% and 33.1%, respectively. A significant, positive and weak correlation was observed between the severity of tinnitus and peripheral sensory neuropathy (ρ = 0.325 and p = 0.001), as well as very weak between the number of complete cycles of chemotherapy and tinnitus (ρ = 0.195 and p = 0.009) and neuropathy peripheral sensory (ρ = 0.237 and p = 0.002). Conclusions: Tinnitus and peripheral sensory neuropathy were frequent toxicities during chemotherapy treatment of breast cancer, and both manifested with low severity/functional impact in most participants.
... The RT-induced SNHL usually presents clinically at least 12 months after completing RT (17,19). However, the SNHL may begin as early as after the completion of RT (20). An increased hearing threshold was observed only in high frequencies at one-month post-radiation. ...
... The hearing threshold of speech frequencies was later increased, at 12, 24, and 60 months post-radiation (16). Incidence of hearing loss after treatment for NPC with RT was 37-85.5% (16,(20)(21)(22), with intensitymodulated radiation therapy (IMRT) was 37% to 51.2% at high frequencies and 6% to 22% at low frequencies (23). Cochlear radiation at doses above and below 60.5 Gy showed significantly increased 5-year and 10-year actuarial risk of clinically overt SNHL at 37% and 3% (24). ...
... Among the cell lines derived from Immortomouse TM inner ear there are the OC-k3 (Organ of Corti-k3) [47], the HEI-OC1 (House Ear Institute-Organ of Corti 1) [48] and the UB/OC-1 (University of Bristol-Organ of Corti 1) [49]. All these cell lines have been employed in cisplatin toxicity investigations demonstrating both cisplatin-induced redox unbalance and protective effects of antioxidant molecules [50][51][52][53][54][55]. Cisplatin acts as a DNA cross linker, binding to purine bases and inhibiting cell proliferation and cell cycle, causing apoptosis of tumour cells [11]. ...
Objective
Highlight the novelties of cisplatin ototoxicity and its prevention, focussing on the role of oxidative stress.
Methods
We screened various electronic databases and selected the reports concerning clinical data and animal and in vitro models investigations related to cisplatin-induced ototoxicity and or its prevention by antioxidants.
Results
Clinical evidence showed that great advances have been made in the chemotherapy outcomes; nevertheless, the ototoxicity, mainly in paediatric patients, is a crucial issue that must be solved. In vitro and in vivo models were pivotal to deeply describe the toxic effect of the cisplatin and which are the mechanisms of action. These knowledges will help the researcher to improve the chemotherapy protocols in order to avoid the adverse effects without compromise the antitumoral action.
Conclusion
Antioxidants seem to be the most promising drugs among the large number of substances tested against cisplatin ototoxicity, however, the inflammatory pathway must be taken into consideration.
... In the etiology of SSHL, apoptosis of the cochlear hair cells occurs during the possibility of the upstream activation of p53 after cisplatin and radiation therapy, and synergistic ototoxicity is seen clinically. 12,13 Radiation-induced changes, including degeneration, epithelial atrophy, and progressive fibrosis of the perilymphatic spaces within the cochlea, were found in pathological studies and on high-resolution computed tomography. 14,15 High-frequency SSHL is significantly associated with the concurrent dose of cisplatin and the mean cochlear radiation dose in NPC. ...
Background:
The aim of this study was to compare the risk of developing sudden sensorineural hearing loss (SSHL) in patients with hypopharyngeal cancer with that in patients with nasopharyngeal carcinoma (NPC).
Methods:
A population-based, retrospective cohort study was performed using the Taiwan National Health Research Database databank. Patients selected for this study were diagnosed with hypopharyngeal cancer or NPC and treated with radiotherapy in the period from 2001 to 2004. Routine follow-up was conducted for 8 years (2004-2012), and the incidence of SSNL was calculated at the final follow-up.
Results:
There was no significant difference in the risk of developing SSHL between the hypopharyngeal cancer group and its control group (p = 1.000). In hypopharyngeal cancer and NPC groups, the rates of SSHL were 0.12% and 1.00%, respectively (p < 0.001). The cumulative hazard of SSHL during the follow-up period was significantly higher in the NPC group than in the control group (p < 0.001).
Conclusion:
Radiotherapy in patients with hypopharyngeal cancer did not increase the risk of developing SSHL, but post-irradiation NPC was significantly associated with an increased incidence of SSHL.
... In their path to hair cells, in the organ of corti, and the sensorial epithelium in the vestibule, ototoxic drugs ototoxic drugs are to go through blood labyrinth membranes [2][3][4]9,12,[18][19][20][21][22][23][24][25]. ...
... The research of inner ear diseases, including oto-toxicity, promises to elucidate concepts about targeted inner ear therapies. Studying inner ear cellular lesional mechanisms in oto-toxic context has allowed to elucidate several therapeutic possibilities [20][21][22][23][24][25]. ...
... (48). Although the radiation dose limits for cochlea is usually set at <45 Gy, yet, various investigators recommend <35-40 Gy and <30 Gy for adult (49,50) and pediatric patients (51), respectively, while others set the critical threshold at ≥47-55 Gy (50,53,58,59). Differing significantly from these traditional dose limits Hermann et al proposed the 20-25 Gy range as the significant cut off for ≥15 dB change in hearing thresholds in 50% of the irradiated patients (52). ...
... It is well-perceived that the concurrent use of chemotherapy with RT, particularly the cisplatin enhances the locoregional disease control and survival outcomes in many tumor sites including the head and neck (56,57). Cisplatin, as a strong cytotoxic and radio-sensitizing agent, targets the cellular DNA via the production of reactive oxygen radicals and triggering of the apoptotic pathways, which are also common for RT-induced cell killing (58,59). On animal researches, the ototoxic effects of both radiation and cisplatin are shown by targeting similar structures of the cochlea (external and internal hair cells, stria vascularis and nerve ends) (60,61). ...
Radiation-induced sensorineural hearing loss (RI-SNHL) is a progressive and irreversible complication of radiotherapy (RT) or chemoradiotherapy (CRT) of brain or head and neck tumors. Onset and progression times of RI-SNHL may broadly vary depending on the RT technique, dose, and concurrent or adjuvant usage of ototoxic medications, such as cisplatin. Characteristically the high frequencies (≥4 kHz) form the first affected range on a typical audiogram, which may be trailed by impairements in the lower hearing frequencies. RI-SNHL may adversely impact both the academic and social advancement in pediatric age and may deteriorate quality of life measures in all affected patients regardless of their age. Even if not eliminate all, in absence of a unequivocally proven medical treatment to avoid or alleviate the RI-SNHL, utilization of more advanced RT techniques, such as the intensity-modulated RT, and limiting the cochlea doses to ≤40-45 Gy for RT alone,<10 Gy for concurrent RT and cisplatin, and <10-12 Gy for stereotactic radiosurgery applications may demonstrate valuable in minimizing the risk of SNHL development. Furthermore, as reactive oxygen species (ROS) are the essential introductory causatives in RT-induced damage via activating the apoptotic cascade in cochlear hair cells, hopefully the development of novel radioprotective agents with the ability to lessen ROS production may prove beneficial in reducing the cochlear damage, and therefore, RI-SNHL, in near future.
... Ambas modalidades de tratamiento han demostrado generar daño auditivo por medio de la inducción de apoptosis. No obstante, la QRT ha mostrado incrementar la expresión de genes relacionados a la apoptosis comparado a cada tratamiento por sí solo en células cocleares 30 , lo que sería concordante con la mayor frecuencia de ototoxicidad observada en pacientes que reciben esquemas combinados 3 . ...
Platinum analogues, such as cisplatin, and radiotherapy are used separately or in combination to treat several neoplasms in pediatric and adult populations. Nonetheless, the use of these treatments may lead to ototoxicity, especially when these treatments are concomitantly used to treat head and neck cancers, which can manifest as progressive and irreversible hearing loss that decreases quality of life. Several mechanisms have been proposed in order to explain the damage to the auditory structures induced by these treatment modalities, including: reactive oxygen species production and inflammation, leading to cell death. Although several otoprotective strategies have been attempted in humans, their effectiveness and security are unclear. The objective of this review is to provide an updated and general overview on platinum-based chemoradio-therapy induced ototoxicity, discussing its basis, clinical features, potential treatments and preventive strategies developed in recent years.
... Ototoxicity was evaluated using in-vitro and in-vivo models. The otic OC-k3 and HEI-OC1 cell lines [43][44][45][46][47][48][49][50] were used as the in-vitro models, in addition to cultures of cochlear epithelia. Although derived from the same tissue and at the same developmental stage, it is possible that these cell lines differ regarding the cell types from which they were derived, as has already been described for similar cell lines 20 . ...
Abstract Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.
... Although there are few studies focused on the side effects of radiotherapy on hearing health, the literature shows a wide variation in the incidence of ototoxicity. 3,7 In both treatments, the higher concentration of toxic substances in the body is able to reach the organ of Corti and sensory epithelia of the posterior labyrinth, through the labyrinthine fluids. These substances compromise mainly the outer hair cells and can lead to cochlear symptoms; however, vestibular disorders may arise in a slow or insidious way, even after the end of treatment. ...
Introduction:
Chemotherapy and radiotherapy in oncology have repercussions in hearing health, and can damage structures of the inner ear. These repercussions usually, result in a bilateral and irreversible hearing loss.
Objective:
To identify sensorineural hearing loss cases with complaints of tinnitus and difficulty in speech understanding and investigate their relationship with the types of chemotherapy and radiotherapy the patients received.
Methods:
Cross-sectional, clinical, observational, analytical, historical cohort study of 58 subjects treated in a public hospital in the state of Sergipe, diagnosed with neoplasia. The subjects were submitted to anamnesis, conventional pure tone audiometry, and speech recognition threshold.
Results:
Of the 116 ears, 25.9% presented sensorioneural hearing loss characterized by changes in high frequencies. There was a positive correlation between hearing loss and the association of chemotherapy and radiotherapy (p=0.035; R=0.196). The auditory complaint analysis shows that most of the subjects had tinnitus and speech understanding difficulty, even with a normal auditory threshold.
Conclusions:
Cancer treatment causes hearing loss, associated with the administration of chemotherapy and radiotherapy. Cyclophosphamide increased the risk of causing hearing loss. Complaints of tinnitus and speech understanding difficulty were observed.
