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ORIGINAL ARTICLE
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Cabazitaxel's ototoxicity: An animal study and histopathologic research


1 Department of Ear Nose and Throat Head and Neck Diseases, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
2 Department of Pathology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
3 Department of Ear Nose and Throat Head and Neck Diseases, Afyonkarahisar State Hospital, Afyonkarahisar, Turkey

Date of Submission12-May-2021
Date of Acceptance02-Jul-2021
Date of Web Publication28-Jan-2022

Correspondence Address:
Abdullah Kınar,
Orhangazi Mah. Nedim Helvacıoğlu Cad. No: 73, Pk. 03020 Afyonkarahisar
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_774_21

 > Abstract 


Introduction: Chemotherapeutic agents can have both serious side effects and ototoxicity, which can be caused by direct toxic effects or by metabolic derangement by the agents. Cabazitaxel (CBZ) is a next-generation semi-synthetic taxane derivative that is effective in both preclinical models of human tumors that are sensitive or resistant to chemotherapy and in patients suffering from progressive prostate cancer despite docetaxel treatment. The primary aim of this study is to investigate the ototoxicity of CBZ in a rat model. Materials and Methods: A total of 24 adult male Wistar-Albino rats were equally and randomly divided into four groups. CBZ (Jevtana, Sanofi-Aventis USA) was intraperitoneally administered to Groups 2, 3, and 4 at doses of 0.5, 1.0, and 1.5 mg/kg/week, respectively, for 4 consecutive weeks; Group 1 received only i.p. saline at the same time. At the end of the study, the animals were sacrificed and their cochlea removed for histopathological examination. Results: Intraperitoneal administration of CBZ exerted an ototoxic effect on rats, and the histopathological results became worse in a dose-dependent manner (P < 0.05). Conclusion: Our findings suggest that CBZ may be an ototoxic agent and can damage the cochlea. More clinical studies should be conducted to understand its ototoxicity.

Keywords: Cabazitaxel, cochlea, hearing, histopathologic, microtubule inhibitor, ototoxic, taxanes



How to cite this URL:
Bucak A, Özdemir &, Kınar A, Ulu &, Kuzu S, Günebakan &, Kahveci OK. Cabazitaxel's ototoxicity: An animal study and histopathologic research. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 8]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=336703




 > Introduction Top


Taxanes are well-recognized anticancer agents and commonly used in the treatment of adult solid cancers. Cabazitaxel (CBZ) is a new generation, small molecule compound, anticancer agent that belongs to the chemical semi-synthetic taxane class. CBZ is an anti-tubulin substance, whose properties and mode of action are similar to first-generation taxanes (paclitaxel and docetaxel). It acts through a tubulin stabilization mechanism that leads to cell death, and it has been designed to overcome the resistance faced by first-generation taxanes that are caused by multi-drug resistant proteins such as P-glycoprotein (P-gp). CBZ is efficient in preclinical models of both chemotherapy-sensitive and resistant human cancers.[1],[2]

CBZ is used as chemotherapy in patients with metastatic castration-resistant prostate cancer that progresses after docetaxel therapy, and it is associated with side effects that may require dose reduction or the discontinuation of treatment.[3],[4]

Although some of the taxanes have been shown to be ototoxic,[5],[6] CBZ is widely used in current clinical practice and its rate of use is gradually increasing, yet there is no information about its ototoxicity. In the present study, CBZ-induced ototoxicity in rats was evaluated by histopathological analysis.


 > Materials And Methods Top


The protocol of this study was approved by the Ethical Committee on Animal Research of (An University) and followed the guidelines of the Central Ethical Committee of Animal Studies of the Ministry of Agriculture and Forestry of the Republic of (That Country). The study was conducted at the Experimental Animal Studies Laboratory of the veterinary faculty of the university. The ethical standards enforced there are in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals and World Medical Association declaration of Helsinki on Ethical Principles for Medical Research Involving Humans for studies involving experimental animals and human beings, respectively.

Animals and drugs

In this study, 24 adult male Wistar-Albino rats weighing 260 ± 20 g were used. All of the rats were examined by a veterinarian and determined to be in good health. The animals were housed in separate plastic cages at a constant temperature of 22°C ± 1°C and at 50% humidity. They were maintained in a 12-h light/dark cycle environment (lights on 7:00–19:00 h), with free access to water and food ad libitum until the end of the study.

The animals were anesthetized with ketamine hydrochloride (Ketalar; Eczacibasi Ilac Sanayi ve Ticaret A. S., Luleburgaz, Turkey) and xylazine (Alfazyne; Alfasan International B. V., Woerden, Netherlands). CBZ (Jevtana, Sanofi-Aventis, USA) was also administered during the study.

Study groups and procedures

The animals were equally and randomly divided into four groups. CBZ was intraperitoneally (i. p.) administered for 4 consecutive weeks to the rats in Groups 2, 3, and 4 in doses of, respectively, 0.5, 1.0, and 1.5 mg per kg of body weight per week; Group 1 was given only i. p. saline at the same time. Intraperitoneal injection was preferred because it is the most commonly used procedure for drug administration to laboratory rodents in experimental studies. At the end of the experimental protocol, a lethal dose of ketamine hydrochloride was administered intraperitoneally and the animals thus sacrificed. The temporal bones were then harvested for histopathological analysis.

Cochlear histopathological analysis

The cochlear bone capsule was located and removed by microdissection using an operating microscope (S100, 250-mm lens; Carl Zeiss, Oberkochen, Germany) by an ear, nose, and throat specialist (A. B.). The samples were fixed with 10% buffered formaldehyde for 3 days, and decalcification was performed using 10% ethylenediaminetetraacetic acid 2Na (pH 7.4). After 3 h, running water was used to wash away the decalcification solution, and the tissue was fixed for 2 more days in formaldehyde. Using a surgical microscope, the remaining extracochlear tissue was removed with a size 15 scalpel, and paraffin-embedded tissues were then sectioned at thickness of 4-μm. The sections were stained with hematoxylin and eosin and evaluated using the light microscopy by a pathologist (C. O.) who was blind to the treatment groups.

The stria vascularis (SV), spiral limbus (SL), and organ of corti (OC) were visualized with a light microscope (Olympus C × 51; Olympus Corp., Tokyo, Japan) at × 3400 and photomicrographed with a Nikon Eclipse e600 (Nikon Corp., Tokyo, Japan) digital camera capture system.

Grading of the OC was based on an assessment of the auditory outer hair cells (OHCs) injury, similar to that described by de Freitas et al. and Bucak et al.[6] A score from 0 to 3 was given equal to the number of injured OHCs.

Injuries to the SV and SL were subjectively evaluated using the staging system described in Bucak et al.[6] which included nuclear degeneration, cytoplasmic vacuolization, and atrophy of intermediate cells (shrinkage). The tissues were categorized as follows: Normal thickness of the SV with no nuclear degeneration, cytoplasmic vacuolization, or shrinkage, scores were derived semi-quantitatively using light microscopy with a modified Quick score method and were reported as follows: 0 (−) negative damage and natural control group, (+1) weak injury, (+2) moderate injury, (+3) severe injury, and (+4) very severe injury.

Statistical analyses

The data were analyzed using the SPSS software 22 (IBM Company, New York, USA) for Windows. Descriptive statistics were expressed as median (range). For the morphological analysis, statistical comparisons of the continuous variables between the groups were performed using the Kruskal–Wallis test due to their nonnormal distributions. ANOVA and Tukey tests were used for post hoc analysis. In cases in which the Kruskal–Wallis test yielded statistical significance, a Bonferroni-corrected Mann–Whitney U-test was used to identify the groups that showed differences. P <0.05 was considered statistically significant.


 > Results Top


A significant relationship was found between CBZ doses and the pathological parameters with SV. SL and OHCs damage grades increasing with greater CBZ dosage.[Table 1]. Post hoc pairwise comparisons were then used to investigate this dose dependent relationship; the pathological grade scores in Groups 2, 3, and 4 were all significantly higher than those in Group 1, and the SL grades were significantly higher in Group 4 than in Groups 2 and 3 (P < 0.05) [Table 1]. The SL is therefore significantly more vulnerable to damage with increasing CBZ doses than the SV and OHCs (P < 0.05) [Figure 1].
Table 1: All pairwise comparisons of cabazitaxel doses (0.5 mg/kg, 1 mg/kg, 1.5 mg/kg) with control group statistically significant. Spiral limbus is significantly more vulnerable to damage with increasing CBZ doses than the SV and OHCs (P<0.05).

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Figure 1: Cabazitaxel doses and spiral limbus, outer hair cells, stria vascularis damage grades shown in the figure. In section A: control group, in section B: grade 2 degenerations, in section C: grade 3 degenerations shown in the figure. In section 1: damage to cochleas, In section 2: damages to spiral limbus, In section 3: damages to stria vascularis shown in the figure. Cabazitaxel damaged the stria vascularis, spiral limbus and outer hair cells of the cochlea in a dose-dependent manner in our study. Loss of outer hair cells in cochlea is seen with increasing cabazitaxel doses in section 1

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 > Discussion Top


Chemotherapy resistance is a major obstacle to successful cancer treatment and the development of new antimicrotubular agents to overcome common mechanisms of resistance is a priority. To overcome taxane resistance via P-gp, docetaxel derivative libraries were screened using docetaxel resistance models and this screening yielded CBZ.[7] Unlike other taxanes, CBZ has a poor affinity for the P-gp-dependent drug outflow pump, which enables activity in cancers that are resistant to other taxanes.[8]

CBZ can be used safely and effectively, taking into consideration the patient's tolerance to the adverse effects of chemotherapy. The major limitation is the myelosuppressive effects, especially neutropenia, which is the most frequent adverse reaction to CBZ administration and the most frequent reason for early cessation of treatment. Less common toxicities are nonhematological, such as diarrhea, nausea, vomiting, and fatigue.[4]

The first taxane, paclitaxel, does not cross the blood–brain barrier (BBB); it specifically affects the peripheral system, leading to a predominantly sensory axonal neuropathy, which is well recognized as the most important nonhematological adverse effect of paclitaxel therapy. It has been reported that CBZ has more effective penetration of the BBB and can diffuse into the brain; interestingly, the neurotoxic effect of CBZ is less than first-generation taxanes, such as docetaxel and paclitaxel.[7]

Although CBZ is an effective anticancer drug and its clinical use is gradually increasing, there is not enough information about its adverse effects and toxicity profile. Some publications have argued a relationship between ototoxicity and paclitaxel. [5, 6, 9, 10] and this was also detected by Bucak et al.[6] using otoacoustic emissions, histopathological evaluation, and immunohistochemical staining, yet, to our knowledge, no previous study has examined whether CBZ administration is ototoxic.

In this study, we used histopathological evaluation to examine whether CBZ could induce ototoxicity in rats resembling the human model. The results show that CBZ administration can induce ototoxicity, depending on the dose.


 > Conclusion Top


In this study, we showed that CBZ can induce ototoxicity by evaluating histopathological changes in the rat cochlea. CBZ damaged the SV, SL, and outer hair cells of the cochlea in a dose-dependent manner in our animal study. However, it is currently uncertain whether CBZ is ototoxic for patients, and more animal studies and multicenter and clinical trials are needed to answer that question. We believe that the potential ototoxicity of CBZ administration in clinical use should be considered and the hearing levels of CBZ-treated patients monitored. The potential ototoxicity of CBZ should also be considered in combination regimens with other taxanes and chemotherapeutics.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010;376:1147-54.  Back to cited text no. 1
    
2.
Nightingale G, Ryu J. Cabazitaxel (jevtana): A novel agent for metastatic castration-resistant prostate cancer. P T 2012;37:440-8.  Back to cited text no. 2
    
3.
Diéras V, Lortholary A, Laurence V, Delva R, Girre V, Livartowski A, et al. Cabazitaxel in patients with advanced solid tumours: Results of a Phase I and pharmacokinetic study. Eur J Cancer 2013;49:25-34.  Back to cited text no. 3
    
4.
Heidenreich A, Bracarda S, Mason M, Ozen H, Sengelov L, Van Oort I, et al. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: Results of the European compassionate-use programme. Eur J Cancer 2014;50:1090-9.  Back to cited text no. 4
    
5.
Sarafraz M, Ahmadi K. Paraclinical evaluation of side-effects of Taxanes on auditory system. Acta Otorhinolaryngol Ital 2008;28:239-42.  Back to cited text no. 5
    
6.
Bucak A, Ozdemir C, Gonul US, Aycicek A, Uysal M, Cangal A. Investigation of protective role of curcumin against paclitaxel-induced inner ear damage in rats. Laryngoscope 2015;125:1175-82.  Back to cited text no. 6
    
7.
Mita AC, Denis LJ, Rowinsky EK, Debono JS, Goetz AD, Ochoa L, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009;15:723-30.  Back to cited text no. 7
    
8.
Sartor O, Michels RM, Massard C, de Bono JS. Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting. Oncologist 2011;16:1487-97.  Back to cited text no. 8
    
9.
Atas A, Agca O, Sarac S, Poyraz A, Akyol MU. Investigation of ototoxic effects of Taxol on a mice model. Int J Pediatr Otorhinolaryngol 2006;70:779-84.  Back to cited text no. 9
    
10.
Dong Y, Ding D, Jiang H, Shi JR, Salvi R, Roth JA. Ototoxicity of paclitaxel in rat cochlear organotypic cultures. Toxicol Appl Pharmacol 2014;280:526-33.  Back to cited text no. 10
    


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