Cisplatina e ototoxicidade na infância: perspectiva de substâncias otoprotetoras coadjuvantes

Araujo, A. G. F. S.; Silva, J. C.; Trindade Filho, E. M.; Silva, J. C.; Gama, K. D. A.; Bandeira, M. A. M.; Silva, W. A.; Mousinho, K. C.

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Brazilian Journal of Biology

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Original Article • Braz. J. Biol. 84 • 2024 • https://doi.org/10.1590/1519-6984.279117 copiar

Cisplatina e ototoxicidade na infância: perspectiva de substâncias otoprotetoras coadjuvantes

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Cisplatina é um antineoplásico utilizado para o tratamento de diversos tipos de câncer. Dentre os efeitos colaterais está a ototoxicidadeque pode acarretar a perda auditiva bilateral e irreversível. O efeito ototóxico na população pediátrica tem impacto maior ao comprometer a aquisição da linguagem. A descoberta de drogas com efeito otoprotetor e a melhor forma de administrá-las tornaram-se grandes desafios para minimizar o impacto da cisplatina a respeito da função auditiva. O objetivo foi conhecer as drogas otoprotetoras e sua relevância no tratamento preventivo da ototoxicidade mediada pelo uso da cisplatina na infância. A revisão integrativa foi realizada através da consulta as bases de dados Pubmed, Bireme, MedLine, LILACS, SciELO e ClinicalTrials.gov. A estratégia de busca foi realizada ao cruzar os descritores (DeCS e MeSH) e os termos livres. Foram selecionados estudos publicados em inglês, espanhol e português, não havendo restrição do ano de publicação. Posteriormente, os artigos foram selecionados de acordo com os critérios de inclusão e exclusão. Foram encontrados 736 artigos na Pubmed, 431 na Bireme, 425 na MedLine, 6 na LILACS, 0 na SciELO e 4 na ClinicalTrials.gov. Após a análise dos documentos foram selecionados 12 artigos para análise na íntegra. Foram encontradas evidências de 8 substâncias com potencial efeito otoprotetor quando usadas com a cisplatina, as quais tendem a minimizar o impacto do efeito da cisplatina sobre a função auditiva. As substâncias encontradas foram: Amifostina, Dexametasona, Genisteína, Ginkgo Biloba, Licopeno, N-acetilcisteína, Polidatinae Tiossulfato de Sódio. Em geral, essas drogas são aplicadas antes, durante ou depois da infusão de cisplatina, a depender da droga escolhida, com administração de maneira intravenosa, via oral ou por injeções transtimpânicas, agindo como terapia antioxidante. Os efeitos bioquímicos dessas substâncias são relevantes para os seus potenciaisotoprotetores, incluindo a inativação de radicais livres de oxigênio e espécies eletrofílicas de platina. O uso dessas substâncias pode reduzir a ototoxicidade, diminuindo a perda auditiva induzida pela cisplatina e aumentando o conforto de vida, especialmente para crianças.

Palavras-chave:
antineoplásicos; prevenção; ototoxicidade; criança

Study	Title			Objective	Author/Local
1	Sodium Thiosulfate for Protection Against Cisplatin-Induced Hearing Loss.			To investigate whether the late administration for Sodium Thiosulfate would reduce the incidence and severity of cisplatin-induced hearing loss.	Brock et al. (2018)BROCK, P.R., MAIBACH, R., CHILDS, M., RAJPUT, K., ROEBUCK, D., SULLIVAN, M.J., LAITHIER, V., RONGHE, M., DALL’IGNA, P., HIYAMA, E., BRICHARD, B., SKEEN, J., MATEOS, M.E., CAPRA, M., RANGASWAMI, A.A., ANSARI, M., RECHNITZER, C., VEAL, G.J., COVEZZOLI, A., BRUGIÈRES, L., PERILONGO, G., CZAUDERNA, P., MORLAND, B. and NEUWELT, E.A., 2018. Sodium thiosulfate for protection from cisplatin-induced hearing loss. The New England Journal of Medicine, vol. 378, no. 25, pp. 2376-2385. http://doi.org/10.1056/NEJMoa1801109. PMid:29924955. http://doi.org/10.1056/NEJMoa1801109... , United Kingdom.
2	The chemopreventive effect of Ginkgo Biloba 761 extract against cisplatin-induced ototoxicity: a pilot study.			To elucidate the role of Ginkgo Biloba 761 in preventing damage to outer hair cells caused by cisplatin therapy in cancer patients through Distortion Product Otoacoustic Emissions.	Dias et al. (2015)DIAS, M.A., SAMPAIO, A.L., VENOSA, A.R., MENESES, E.A. and OLIVEIRA, C.A., 2015. The chemopreventive effect of Ginkgo biloba extract 761 against cisplatin ototoxicity: a pilot study. The International Tinnitus Journal, vol. 19, no. 2, pp. 12-19. http://doi.org/10.5935/0946-5448.20150003. PMid:27186927. http://doi.org/10.5935/0946-5448.2015000... , Brazil.
3	Are Ginkgo Biloba and Lycopene effective against cisplatin-induced ototoxicity?			Investigate the protective effects of Lycopene and Ginkgo Biloba on cisplatin-induced ototoxicity and compare their advantages to each other	Esen et al. (2018)ESEN, E., ÖZDOĞAN, F., GÜRGEN, S.G., ÖZEL, H.E., BAŞER, S., GENÇ, S. and SELÇUK, A., 2018. Ginkgo biloba and Lycopene are effective on cisplatin induced ototoxicity? The Journal of International Advanced Otology, vol. 14, no. 1, pp. 22-26. http://doi.org/10.5152/iao.2017.3137. PMid:28639555. http://doi.org/10.5152/iao.2017.3137... , Turkiye.
4	Amifostine protects against cisplatin-induced ototoxicity in children with medium-risk medulloblastoma.			To investigate the ability of Amifostine to protect children receiving a high-dose cisplatin-based regimen against severe ototoxicity, defined as ototoxicity ≥ grade 3 that requires hearing aids in at least one ear, next to one year the start of treatment.	Fouladi et al. (2008)FOULADI, M., CHINTAGUMPALA, M., ASHLEY, D., KELLIE, S., GURURANGAN, S., HASSALL, T., GRONEWOLD, L., STEWART, C.F., WALLACE, D., BRONISCER, A., HALE, G.A., KASOW, K.A., MERCHANT, T.E., MORRIS, B., KRASIN, M., KUN, L.E., BOYETT, J.M. and GAJJAR, A., 2008. Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. Journal of Clinical Oncology, vol. 26, no. 22, pp. 3749-3755. http://doi.org/10.1200/JCO.2007.14.3974. PMid:18669462. http://doi.org/10.1200/JCO.2007.14.3974... , Tennessee.
5	Effects of Sodium Thiosulfate vs. Observation on the Development of Cisplatin-Induced Hearing Loss in Children with Cancer: Results from the ACCL0431 Pediatric Oncology Group Randomized Clinical Trial.			Compare the proportional incidence of post-treatment cisplatin-induced hearing loss between those randomized to receive or not receive Sodium Thiosulfate.	Freyer et al. (2017)FREYER, D.R., CHEN, L., KRAILO, M.D., KNIGHT, K., VILLALUNA, D., BLISS, B., POLLOCK, B.H., RAMDAS, J., LANGE, B., VAN HOFF, D., VANSOELEN, M.L., WIERNIKOWSKI, J., NEUWELT, E.A. and SUNG, L., 2017. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer: results from the children’s oncology group ACCL0431 randomised clinical trial. The Lancet. Oncology, vol. 18, no. 1, pp. 63-74. http://doi.org/10.1016/S1470-2045(16)30625-8. PMid:27914822. http://doi.org/10.1016/S1470-2045(16)306... , California.
6	Evaluation of Amifostine for Protection Against Severe Cisplatin-Induced Hearing Loss in Children Treated for Medium or High-Risk Medulloblastoma.			Evaluation for Amifostine for Protection Against Severe Cisplatin-Induced Hearing Loss in Children Treated to Medium or High-Risk Medulloblastoma.	Gurney et al. (2014)GURNEY, J., BASS, J.K., ONAR-THOMAS, A., HUANG, J., CHINTAGUMPALA, M., BOUFFET, E., HASSALL, T., GURURANGAN, S., HEATH, J.A., KELLIE, S., COHN, R., FISHER, M.J., PANANDIKER, A.P., MERCHANT, T.E., SRINIVASAN, A., WETMORE, C., QADDOUMI, I., STEWART, C.F., ARMSTRONG, G.T., BRONISCER, A. and GAJJAR, A., 2014. Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma. Neuro-Oncology, vol. 16, no. 6, pp. 848-855. http://doi.org/10.1093/neuonc/not241. PMid:24414535. http://doi.org/10.1093/neuonc/not241... , Tennessee.
7	Amifostine Otoprotection Against Cisplatin Ototoxic Effects: Study in Albino Guinea Pigs Using Distortion Product Otoacoustic Emissions and Scanning Electron Microscopy.			Assessing the Potential Otoprotective Effect of Amifostine in Cisplatin Treatment through Distortion Product Otoacoustic Emissions (DPOAE) and Scanning Electron Microscopy (SEM).	Hyppolito et al. (2005)HYPPOLITO, M.A., DE OLIVEIRA, A.A., LESSA, R.M. and ROSSATO, M., 2005. Amifostineotoprotection to cisplatin ototoxicity: a guinea pig study using otoacoustic emission distortion products (DPOEA) and scanning electron microscopy. Revista Brasileira de Otorrinolaringologia, vol. 71, no. 3, pp. 268-273. PMid:16446928., Brazil.
8	Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma. A report from the Intergroup Hepatoblastoma Study P9645 as part of the Children's Oncology Group.			To determine whether Amifostine is effective in reducing toxicities associated with the administration of platinum-containing regimens to young people with hepatoblastoma.	Katzenstein et al. (2009)KATZENSTEIN, H., CHANG, K.W., KRAILO, M., CHEN, Z., FINEGOLD, M.J., ROWLAND, J., REYNOLDS, M., PAPPO, A., LONDON, W.B. and MALOGOLOWKIN, M., 2009. Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma. A report of the Intergroup Hepatoblastoma Study P9645 as a part of the Children’s Oncology Group. Cancer, vol. 115, no. 24, pp. 5828-5835. http://doi.org/10.1002/cncr.24667. PMid:19813275. http://doi.org/10.1002/cncr.24667... , California.
9	Polidatina activates the Nrf2/HO-1 signaling pathway to protect against cisplatin-induced hearing loss in guinea pigs.			Exploring the effects of Polidatina on cisplatin-induced hearing loss and attempting to unravel the underlying mechanism.	Li et al. (2022)LI, D., ZHAO, H., XU, P., LIN, Q., ZHAO, T., LI, C., CUI, Z.K. and TIAN, G., 2022. Polydatin activates the Nrf2/HO-1 signaling pathway to protect cisplatin-induced hearing loss in guinea pigs. Frontiers in Pharmacology, vol. 13, pp. 887833. PMid:35991886., China.
10	Amifostine doesn't protect against cisplatin ototoxicity at high doses combined with etoposide and bleomycin in pediatric germ cell tumors.			To determine if pretreatment with Amifostine reduced the significant ototoxicity associated with drugs while maintaining its survival advantage.	Marina et al. (2005)MARINA, N., CHANG, K.W., MALOGOLOWKIN, M., LONDON, W.B., FRAZIER, A.L., WOMER, R.B., RESCORLA, F., BILLMIRE, D.F., DAVIS, M.M., PERLMAN, E.J., GILLER, R., LAUER, S.J. and OLSON, T.A., 2005. Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors. Cancer, vol. 104, no. 4, pp. 841-847. http://doi.org/10.1002/cncr.21218. PMid:15999362. http://doi.org/10.1002/cncr.21218... , California.
11	Transtympanic injections of N-acetylcysteine and Dexamethasone for the prevention of cisplatin-induced ototoxicity: a double-blind randomized clinical trial.			Comparing the positive effects of intratympanic injection for N-acetylcysteine and Dexamethasone in preventing cisplatin-induced ototoxicity.	Sarafraz et al. (2018)SARAFRAZ, Z., AHMADI, A. and DANESHI, A., 2018. Transtympanic injections of N-acetylcysteine and dexamethasone for prevention of cisplatin-induced ototoxicity: double blind randomized clinical Trial. The International Tinnitus Journal, vol. 22, no. 1, pp. 40-45. http://doi.org/10.5935/0946-5448.20180007. PMid:29993216. http://doi.org/10.5935/0946-5448.2018000... , Iran.
12		Effect of Genistein on cisplatin-induced ototoxicity and oxidative stress.	Evaluate the otoprotective effect of Genistein against cisplatin in rats.			Tan et al. (2022)TAN, M., TOPLU, Y., VARAN, E., SAPMAZ, E., ÖZHAN, O., PARLAKPINAR, H. and POLAT, A., 2022. The effect of genistein on cisplatininduced ototoxicity and oxidative stress. Revista Brasileira de Otorrinolaringologia, vol. 88, no. 1, pp. 105-111. PMid:34602350., Turkiye.

Study	Drug	Typeofstudy	Level os scientificevidence	Conclusion
1	Sodium Thiosulfate	Cohortstudy	2B	Sodium thiosulfate following cisplatin chemotherapy resulted in a lower incidence for cisplatin-induced hearing loss in young people with hepatoblastoma.
2	Ginkgo Biloba	Cohortstudy	2B	Ginkgo Biloba, when administered at 240 mg per day, demonstrated otoprotective effects against cisplatin-induced damage.
3	Ginkgo Biloba e Lycopene	Cohortstudy	2B	There is a protective effect of Ginkgo Biloba and Lycopene in a cisplatin-dependent ototoxic rat model.
4	Amifostine	Cohortstudy	2B	Amifostine administered before and during cisplatin infusion can significantly reduce the risk for ototoxicity in patients with medulloblastoma.
3	Sodium Thiosulfate	Cohortstudy	2B	The studied drug provides protection against cisplatin-induced hearing loss in young people and is not associated with severe adverse events attributed to its use.
6	Amifostine	Cohortstudy	2B	Amifostine provides protection against severe cisplatin-induced hearing loss in patients with moderate-risk medulloblastoma.
7	Amifostine	Control case study	3A	Amifostine demonstrates clear signs of otoprotection against the ototoxic effects produced by cisplatin in albino guinea pigs.
8	Amifostine	Cohortstudy	2B	In this study, Amifostine failed to significantly reduce the incidence of platinum-induced toxicity in patients with hepatoblastoma.
9	Polydatin	Cohortstudy	2B	Polidatina, as a natural extract from traditional Chinese medicine, may alleviate cisplatin-induced hearing loss.
10	Amifostine	Cohortstudy	2B	Amifostine didn’t protect against cisplatin-associated ototoxicity at high doses combined with etoposide and bleomycin.
11	N-acetylcysteine and Dexamethasone	Cohortstudy	2B	N-acetylcysteine injections as an antioxidant agent appear to be an effective otoprotective strategy for preventing cisplatin-induced ototoxicity.
12	Genistein	Cohortstudy	2B	Genistein exhibited positive effects against ototoxicity due to its antioxidant effect.

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