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Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2020.tde-05062020-085550
Document
Author
Full name
Vanessa Foresto Machado
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Feres, Omar (President)
Garcia, Sergio Britto
Nadal, Sidney Roberto
Rocha, Jose Joaquim Ribeiro da
Title in Portuguese
Avaliação da carcinogênese retal induzida por N-Metil-N-nitrosoguanidina e efeito da oxigenoterapia hiperbárica adjuvante à quimioterapia
Keywords in Portuguese
Neoplasia colorretal
Oxigênio hiperbárico
Quimioterapia
Abstract in Portuguese
INTRODUÇÃO: a hipóxia tumoral pode comprometer o resultado da quimioterapia no tratamento do câncer colorretal devido a estímulo de angiogênese e liberação de fatores de crescimento tumoral. A suplementação de oxigênio em regime hiperbárico pode potencializar o efeito da quimioterapia nesses casos. OBJETIVO: avaliar o efeito da oxigenoterapia hiperbárica combinada à quimioterapia no tratamento de câncer colorretal em camundongos. METODOLOGIA: Trata-se de um estudo experimental com 60 camundongos C57BL6 que foram divididos em 5 grupos: 1) grupo controle: 15 animais submetidos a instilação de solução salina intrarretal, 2) grupo MNNG:15 animais submetidos a instilação de MNNG intrarretal, 3) grupo 5FU: 10 animais submetidos a instilação de MNNG intrarretal e tratados com 5-fluororacil (5FU), 4) grupo OHB: 10 animais submetidos à instilação de MNNG intrarretal e tratados com oxigenoterapia hiperbárica (OHB), 5) grupo 5FU+OHB: 10 animais submetidos a instilação de MNNG intrarretal e tratamento com 5FU e OHB. Os grupos controle e carcinógeno foram avaliados com exame endoscópico nas semanas 4 e 8 e a eutanásia foi realizada após 12 semanas. Os demais grupos passaram por exame endoscópico na semana 12 e, após, foram tratados por 2 semanas antes da eutanásia. Os cólons dos animais foram removidos para análise histológica e imunohistoquimica com dosagem de BAX, HIF1α, CD44 e survivina. RESULTADOS: o grupo MNNG apresentou a maior taxa de criptas displásicas (8,6%, p<0,0001) e a menor taxa de criptas necróticas (0,13%, p<0,0001). O grupo 5FU+OHB apresentou a maior taxa de células apoptóticas por cripta displásica (10,4%, p<0,0001) e maior taxa de espaços criptais vazios (3,1%, p<0,0001). O grupo 5FU apresentou a maior expressão de HIF1α (11%, p<0,0001), CD44 (6,5%, p<0,0001) e survivina (14,1%, p<0,0001). A expressão de BAX foi maior no grupo 5FU+OHB (20,2%, p<0,05). CONCLUSÃO: a oxigenoterapia hiperbárica potencializou o efeito do 5-FU no tratamento de neoplasia colorretal experimental em camundongos.
Title in English
Evaluation of retal carcinogenesis induced by N-metil-N-nitrosoguanidine and effect of adjuvant hyperbaric oxygenotherapy on chemotherapy
Keywords in English
Chemotherapy
Colorectal cancer
Hyperbaric oxygen
Abstract in English
Introduction: Tumor hypoxia may compromise the efficacy of chemotherapy in the treatment of colorectal cancer due to the stimulation to angiogenesis and release of tumor growth factors. Hyperbaric oxygen (HBO) supplementation may increase the effect of chemotherapy in these cases. Objective: to evaluate the effect of combined hyperbaric oxygen therapy and 5-fluorouracil (5FU) in the treatment of murine colorectal cancer induced by rectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Methods: 60 C57BL6 mice were divided into 5 groups: 1) CONTROL group- 15 animals submitted to rectal instillation of saline solution; 2) MNNG group - 15 animals submitted to rectal instillation of MNNG; 3) 5FU group - 10 animals submitted to rectal instillation of MNNG and treated with 5FU; 4) HBO group - 10 animals submitted to rectal instillation of MNNG and treated with HBO; and 5) HBO+5FU group - 10 animals submitted to rectal instillation of MNNG and treated with combined HBO and 5FU. Control and MNNG groups were endoscopic evaluated in weeks number 4 and 8 and euthanasia was carried out after 12 weeks. All other groups were endoscopic evaluated after 12 weeks and then treated for 2 weeks before the euthanasia and the removal of the colon. Histological features and immunohistochemical expression (BAX, HIF-1, CD44 and survivin) were performed in all specimens. Results: MNNG group had the highest rate of dysplastic crypts (8.6%, p< 0.0001) and the lowest necrotic crypt index (0.13%; p<0.0001). 5FU+HBO group had the highest index of apoptotic cells by dysplastic crypt (10.4%; p<0.0001) and rate of empty crypt spaces (3.1%; p<0.0001). 5FU group presented the highest expression of HIF1 (11%; p<0.0001), CD44 (6.5%; p<0.0001) and surviving (14.1%; p<0.0001). Expression of BAX was higher in 5FU+OHB group (20.2%; p<0.05). Conclusion: Hyperbaric Oxygen enhanced the effect of 5-FU in the treatment of experimental colorectal cancer.
 
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Publishing Date
2020-07-13
 
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