Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFC |
Texto Completo: | http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=11712 |
Resumo: | Introduction: Intestinal mucositis is a common side effect of anticancer regimens for first-line treatment of colorectal cancer. Among such drugs are irinotecan and 5-FU used in combination. Many studies have been conducted on the pathogenesis of MI. However, further investigations are necessary, because the course of MI may vary according to the drug regimen and employees. Then aimed to develop a new experimental model of MI induced by the combination of IRI and 5-FU in mice. Methods and Results: C57BL/6 mice (20-25g, n=6) were injected with saline (100ÂL, i.p), IRI (30 or 45 mg/kg, i.p), 5-FU (25, 37.5 or 50 mg/kg, i.p) or IRI+5-FU for 4 days. On day 7, diarrhea, weight loss, and blood leukocyte count were registered. Following animal euthanasia, ileum samples were collected for histopathological analysis, myeloperoxidase activity (MPO, neutrophil/mg protein), TNF-α and IL-6 levels (pg/mg tissue). Kaplan-Mayer log rank test, Kruskal Wallis/Dunnâs or ANOVA/Bonferroniâs test was used for statistical analysis. p<0.05 was accepted. The best dose combination able to induce IM with no important mortality on day 7 was 5-FU (37.5 mg/kg) +IRI (45 mg/kg) (0% mortality), which was then used for subsequent studies. IRI+5-FU induced (p<0.001) diarrhea (2[0-3]), weight loss (86.7Â3.9g), and leukopenia (7.3Â 2.3 x103) versus saline group (0[0-1]; 101.1Â0.6; 215.5Â 54.1, respectively) or each drug given alone (5-FU: diarrhea (0[0-1]), weight loss [92.6Â2.7], and leukopenia [30.4Â 13.4]; IRI: diarrhea (0[0-1]), weight loss [94.8Â2.1], and leukopenia [49.2Â 5.5]). In addition, IRI+5-FU induced inflammatory cells infiltration, and loss of villi and crypt architecture (4[3-4]), increased in MPO activity (14641Â1598 neutrophil/mgproteÃn), TNF-a (3.2Â0.9 pg/mg tissue), IL-6 (1.4Â0.5 pg/mg tissue) tissue levels versus saline-injected group (0[0-1], 5747Â1155; 0.7Â0.2; 0.3Â0.1) or the drugs injected alone (5-FU: Intestinal damage (2.5[2-3]), MPO [3788Â1212], TNF-α [0.7Â0.2], IL-6 [0.2Â2.3]; IRI: Intestinal damage (1[0-2]), MPO [3580Â1613], TNF-α [0.4Â0,2], IL-6 [0.07Â0.05]) (p<0.05). Conclusion: We developed a new experimental model of IM induced by the combination of IRI+5-FU in mice, which opens perspective for a more appropriate knowledge concerning the pathogenesis of IM. |
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info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisNovo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/62013-12-05Roberto CÃsar Pereira Lima JÃnior87277123387http://lattes.cnpq.br/8104904120076956Pedro Jorge Caldas MagalhÃes38546620334http://lattes.cnpq.br/0057645238802910Luzia Kalyne Almeida Moreira Leal38259850320http://lattes.cnpq.br/344772815322501601801911363http://lattes.cnpq.br/9284843601128833VenÃcia Bruna MagalhÃes PereiraUniversidade Federal do CearÃPrograma de PÃs-GraduaÃÃo em FarmacologiaUFCBRInflammationMucositisFluorouracilFARMACOLOGIAIntroduction: Intestinal mucositis is a common side effect of anticancer regimens for first-line treatment of colorectal cancer. Among such drugs are irinotecan and 5-FU used in combination. Many studies have been conducted on the pathogenesis of MI. However, further investigations are necessary, because the course of MI may vary according to the drug regimen and employees. Then aimed to develop a new experimental model of MI induced by the combination of IRI and 5-FU in mice. Methods and Results: C57BL/6 mice (20-25g, n=6) were injected with saline (100ÂL, i.p), IRI (30 or 45 mg/kg, i.p), 5-FU (25, 37.5 or 50 mg/kg, i.p) or IRI+5-FU for 4 days. On day 7, diarrhea, weight loss, and blood leukocyte count were registered. Following animal euthanasia, ileum samples were collected for histopathological analysis, myeloperoxidase activity (MPO, neutrophil/mg protein), TNF-α and IL-6 levels (pg/mg tissue). Kaplan-Mayer log rank test, Kruskal Wallis/Dunnâs or ANOVA/Bonferroniâs test was used for statistical analysis. p<0.05 was accepted. The best dose combination able to induce IM with no important mortality on day 7 was 5-FU (37.5 mg/kg) +IRI (45 mg/kg) (0% mortality), which was then used for subsequent studies. IRI+5-FU induced (p<0.001) diarrhea (2[0-3]), weight loss (86.7Â3.9g), and leukopenia (7.3 2.3 x103) versus saline group (0[0-1]; 101.1Â0.6; 215.5 54.1, respectively) or each drug given alone (5-FU: diarrhea (0[0-1]), weight loss [92.6Â2.7], and leukopenia [30.4 13.4]; IRI: diarrhea (0[0-1]), weight loss [94.8Â2.1], and leukopenia [49.2 5.5]). In addition, IRI+5-FU induced inflammatory cells infiltration, and loss of villi and crypt architecture (4[3-4]), increased in MPO activity (14641Â1598 neutrophil/mgproteÃn), TNF-a (3.2Â0.9 pg/mg tissue), IL-6 (1.4Â0.5 pg/mg tissue) tissue levels versus saline-injected group (0[0-1], 5747Â1155; 0.7Â0.2; 0.3Â0.1) or the drugs injected alone (5-FU: Intestinal damage (2.5[2-3]), MPO [3788Â1212], TNF-α [0.7Â0.2], IL-6 [0.2Â2.3]; IRI: Intestinal damage (1[0-2]), MPO [3580Â1613], TNF-α [0.4Â0,2], IL-6 [0.07Â0.05]) (p<0.05). Conclusion: We developed a new experimental model of IM induced by the combination of IRI+5-FU in mice, which opens perspective for a more appropriate knowledge concerning the pathogenesis of IM.IntroduÃÃo: Mucosite intestinal à um efeito adverso comum dos regimes anticÃncer de primeira linha para o tratamento do cÃncer colorretal. Dentre esses fÃrmacos estÃo o irinotecano e 5-FU utilizados em associaÃÃo. Muitos estudos tÃm sido realizados sobre a patogÃnese da MI. No entanto, novas investigaÃÃes sÃo necessarias, pois o curso da MI pode variar de acordo com o fÃrmaco e regime empregados. Objetivou-se entÃo desenvolver um novo modelo experimental de MI induzida pela combinaÃÃo de IRI e 5-FU em camundogos. MÃtodos e Resultados: camundongos C57BL/6 (20-25g, n=6) foram injetados com salina (100ÂL, i.p), IRI (30 ou 45 mg/kg, i.p), 5-FU (25, 37,5 ou 50 mg/kg, i.p) ou IRI+5-FU em doses combinadas por 4 dias. No 7 dia, diarreia, perda de peso e contagem de leucÃcitos foram registradas. ApÃs a eutanÃsia dos animais, amostras do Ãleo foram coletadas para anÃlise histopatolÃgica, atividade de mieloperoxidase (neutrÃfilo/mg proteÃna), nÃveis de TNF-α e IL-6 (pg/mg tecido). Teste Kaplan-Mayer log rank, Kruskal Wallis/Dunnâs ou teste ANOVA/Bonferroni foram usados para analise estatistica. p<0,05 foi aceito como significativo. A melhor combinaÃÃo de dose para induzir a MI sem mortalidade importante no 7 dia foi 5-FU (37,5 mg/kg) + IRI (45 mg/kg) (0% mortalidade), que foi entÃo usada para estudos subsequentes. IRI+5-FU induziu (p<0,001) diarreia (2[0-3]), perda de peso (86,7Â3,9g), e leucopenia (7,3 2,3x103) versus grupo salina (0[0-1]; 101,1Â0,6; 215,5 54,1, respectivamente) ou cada droga dada sozinha (5-FU: diarreia (0[0-1]), perda de peso [92,6Â2,7], e leucopenia [30,4 13,4]; IRI: diarreia (0[0-1]), perda de peso [94,8Â2,1], e leucopenia [49,2 5,5]). Adicionalmente, IRI+5-FU induziu infiltrado de cÃlulas inflamatÃrias, perda de vilos e arquitetura das criptas (4[4-4]), aumento na atividade de MPO (14641Â1598 neutrÃfilo/mgproteÃna), TNF-a (3,2Â0,9 pg/mg de tecido), IL-6 (1,4Â0,5 pg/mg de tecido) nÃveis teciduais versus grupo injetado com salina (0[0-1], 5747Â1155; 0,7Â0,2; 0,3Â0,1) ou com fÃrmacos injetados isoladamente (5-FU: dano intestinal (2.5[2-3]), MPO [3788Â1212], TNF-α [0,7Â0,2], IL-6 [0,2Â2,3]; IRI: dano intestinal (1[0-2]), MPO [3580Â1613], TNF-α [0,4Â0,2], IL-6 [0,07Â0,05]) (p<0,05). ConclusÃo: Desenvolvemos um novo modelo experimental de MI induzida pela combinaÃÃo de IRI+5-FU em camundongos, que abre perspectiva para um maior conhecimento sobre a patogÃnese da MI.Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicohttp://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=11712application/pdfinfo:eu-repo/semantics/openAccessporreponame:Biblioteca Digital de Teses e Dissertações da UFCinstname:Universidade Federal do Cearáinstacron:UFC2019-01-21T11:24:54Zmail@mail.com - |
dc.title.pt.fl_str_mv |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 |
title |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 |
spellingShingle |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 VenÃcia Bruna MagalhÃes Pereira Inflammation Mucositis Fluorouracil FARMACOLOGIA |
title_short |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 |
title_full |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 |
title_fullStr |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 |
title_full_unstemmed |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 |
title_sort |
Novo Modelo de Mucosite Intestinal Induzida pela AssociaÃÃo de Irinotecano e 5-Fluorouracil em Camundongos C57BL/6 |
author |
VenÃcia Bruna MagalhÃes Pereira |
author_facet |
VenÃcia Bruna MagalhÃes Pereira |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Roberto CÃsar Pereira Lima JÃnior |
dc.contributor.advisor1ID.fl_str_mv |
87277123387 |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/8104904120076956 |
dc.contributor.referee1.fl_str_mv |
Pedro Jorge Caldas MagalhÃes |
dc.contributor.referee1ID.fl_str_mv |
38546620334 |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/0057645238802910 |
dc.contributor.referee2.fl_str_mv |
Luzia Kalyne Almeida Moreira Leal |
dc.contributor.referee2ID.fl_str_mv |
38259850320 |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/3447728153225016 |
dc.contributor.authorID.fl_str_mv |
01801911363 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/9284843601128833 |
dc.contributor.author.fl_str_mv |
VenÃcia Bruna MagalhÃes Pereira |
contributor_str_mv |
Roberto CÃsar Pereira Lima JÃnior Pedro Jorge Caldas MagalhÃes Luzia Kalyne Almeida Moreira Leal |
dc.subject.eng.fl_str_mv |
Inflammation Mucositis Fluorouracil |
topic |
Inflammation Mucositis Fluorouracil FARMACOLOGIA |
dc.subject.cnpq.fl_str_mv |
FARMACOLOGIA |
dc.description.sponsorship.fl_txt_mv |
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico |
dc.description.abstract..fl_txt_mv |
Introduction: Intestinal mucositis is a common side effect of anticancer regimens for first-line treatment of colorectal cancer. Among such drugs are irinotecan and 5-FU used in combination. Many studies have been conducted on the pathogenesis of MI. However, further investigations are necessary, because the course of MI may vary according to the drug regimen and employees. Then aimed to develop a new experimental model of MI induced by the combination of IRI and 5-FU in mice. Methods and Results: C57BL/6 mice (20-25g, n=6) were injected with saline (100ÂL, i.p), IRI (30 or 45 mg/kg, i.p), 5-FU (25, 37.5 or 50 mg/kg, i.p) or IRI+5-FU for 4 days. On day 7, diarrhea, weight loss, and blood leukocyte count were registered. Following animal euthanasia, ileum samples were collected for histopathological analysis, myeloperoxidase activity (MPO, neutrophil/mg protein), TNF-α and IL-6 levels (pg/mg tissue). Kaplan-Mayer log rank test, Kruskal Wallis/Dunnâs or ANOVA/Bonferroniâs test was used for statistical analysis. p<0.05 was accepted. The best dose combination able to induce IM with no important mortality on day 7 was 5-FU (37.5 mg/kg) +IRI (45 mg/kg) (0% mortality), which was then used for subsequent studies. IRI+5-FU induced (p<0.001) diarrhea (2[0-3]), weight loss (86.7Â3.9g), and leukopenia (7.3Â 2.3 x103) versus saline group (0[0-1]; 101.1Â0.6; 215.5Â 54.1, respectively) or each drug given alone (5-FU: diarrhea (0[0-1]), weight loss [92.6Â2.7], and leukopenia [30.4Â 13.4]; IRI: diarrhea (0[0-1]), weight loss [94.8Â2.1], and leukopenia [49.2Â 5.5]). In addition, IRI+5-FU induced inflammatory cells infiltration, and loss of villi and crypt architecture (4[3-4]), increased in MPO activity (14641Â1598 neutrophil/mgproteÃn), TNF-a (3.2Â0.9 pg/mg tissue), IL-6 (1.4Â0.5 pg/mg tissue) tissue levels versus saline-injected group (0[0-1], 5747Â1155; 0.7Â0.2; 0.3Â0.1) or the drugs injected alone (5-FU: Intestinal damage (2.5[2-3]), MPO [3788Â1212], TNF-α [0.7Â0.2], IL-6 [0.2Â2.3]; IRI: Intestinal damage (1[0-2]), MPO [3580Â1613], TNF-α [0.4Â0,2], IL-6 [0.07Â0.05]) (p<0.05). Conclusion: We developed a new experimental model of IM induced by the combination of IRI+5-FU in mice, which opens perspective for a more appropriate knowledge concerning the pathogenesis of IM. |
dc.description.abstract.por.fl_txt_mv |
IntroduÃÃo: Mucosite intestinal à um efeito adverso comum dos regimes anticÃncer de primeira linha para o tratamento do cÃncer colorretal. Dentre esses fÃrmacos estÃo o irinotecano e 5-FU utilizados em associaÃÃo. Muitos estudos tÃm sido realizados sobre a patogÃnese da MI. No entanto, novas investigaÃÃes sÃo necessarias, pois o curso da MI pode variar de acordo com o fÃrmaco e regime empregados. Objetivou-se entÃo desenvolver um novo modelo experimental de MI induzida pela combinaÃÃo de IRI e 5-FU em camundogos. MÃtodos e Resultados: camundongos C57BL/6 (20-25g, n=6) foram injetados com salina (100ÂL, i.p), IRI (30 ou 45 mg/kg, i.p), 5-FU (25, 37,5 ou 50 mg/kg, i.p) ou IRI+5-FU em doses combinadas por 4 dias. No 7 dia, diarreia, perda de peso e contagem de leucÃcitos foram registradas. ApÃs a eutanÃsia dos animais, amostras do Ãleo foram coletadas para anÃlise histopatolÃgica, atividade de mieloperoxidase (neutrÃfilo/mg proteÃna), nÃveis de TNF-α e IL-6 (pg/mg tecido). Teste Kaplan-Mayer log rank, Kruskal Wallis/Dunnâs ou teste ANOVA/Bonferroni foram usados para analise estatistica. p<0,05 foi aceito como significativo. A melhor combinaÃÃo de dose para induzir a MI sem mortalidade importante no 7 dia foi 5-FU (37,5 mg/kg) + IRI (45 mg/kg) (0% mortalidade), que foi entÃo usada para estudos subsequentes. IRI+5-FU induziu (p<0,001) diarreia (2[0-3]), perda de peso (86,7Â3,9g), e leucopenia (7,3 2,3x103) versus grupo salina (0[0-1]; 101,1Â0,6; 215,5 54,1, respectivamente) ou cada droga dada sozinha (5-FU: diarreia (0[0-1]), perda de peso [92,6Â2,7], e leucopenia [30,4 13,4]; IRI: diarreia (0[0-1]), perda de peso [94,8Â2,1], e leucopenia [49,2 5,5]). Adicionalmente, IRI+5-FU induziu infiltrado de cÃlulas inflamatÃrias, perda de vilos e arquitetura das criptas (4[4-4]), aumento na atividade de MPO (14641Â1598 neutrÃfilo/mgproteÃna), TNF-a (3,2Â0,9 pg/mg de tecido), IL-6 (1,4Â0,5 pg/mg de tecido) nÃveis teciduais versus grupo injetado com salina (0[0-1], 5747Â1155; 0,7Â0,2; 0,3Â0,1) ou com fÃrmacos injetados isoladamente (5-FU: dano intestinal (2.5[2-3]), MPO [3788Â1212], TNF-α [0,7Â0,2], IL-6 [0,2Â2,3]; IRI: dano intestinal (1[0-2]), MPO [3580Â1613], TNF-α [0,4Â0,2], IL-6 [0,07Â0,05]) (p<0,05). ConclusÃo: Desenvolvemos um novo modelo experimental de MI induzida pela combinaÃÃo de IRI+5-FU em camundongos, que abre perspectiva para um maior conhecimento sobre a patogÃnese da MI. |
description |
Introduction: Intestinal mucositis is a common side effect of anticancer regimens for first-line treatment of colorectal cancer. Among such drugs are irinotecan and 5-FU used in combination. Many studies have been conducted on the pathogenesis of MI. However, further investigations are necessary, because the course of MI may vary according to the drug regimen and employees. Then aimed to develop a new experimental model of MI induced by the combination of IRI and 5-FU in mice. Methods and Results: C57BL/6 mice (20-25g, n=6) were injected with saline (100ÂL, i.p), IRI (30 or 45 mg/kg, i.p), 5-FU (25, 37.5 or 50 mg/kg, i.p) or IRI+5-FU for 4 days. On day 7, diarrhea, weight loss, and blood leukocyte count were registered. Following animal euthanasia, ileum samples were collected for histopathological analysis, myeloperoxidase activity (MPO, neutrophil/mg protein), TNF-α and IL-6 levels (pg/mg tissue). Kaplan-Mayer log rank test, Kruskal Wallis/Dunnâs or ANOVA/Bonferroniâs test was used for statistical analysis. p<0.05 was accepted. The best dose combination able to induce IM with no important mortality on day 7 was 5-FU (37.5 mg/kg) +IRI (45 mg/kg) (0% mortality), which was then used for subsequent studies. IRI+5-FU induced (p<0.001) diarrhea (2[0-3]), weight loss (86.7Â3.9g), and leukopenia (7.3Â 2.3 x103) versus saline group (0[0-1]; 101.1Â0.6; 215.5Â 54.1, respectively) or each drug given alone (5-FU: diarrhea (0[0-1]), weight loss [92.6Â2.7], and leukopenia [30.4Â 13.4]; IRI: diarrhea (0[0-1]), weight loss [94.8Â2.1], and leukopenia [49.2Â 5.5]). In addition, IRI+5-FU induced inflammatory cells infiltration, and loss of villi and crypt architecture (4[3-4]), increased in MPO activity (14641Â1598 neutrophil/mgproteÃn), TNF-a (3.2Â0.9 pg/mg tissue), IL-6 (1.4Â0.5 pg/mg tissue) tissue levels versus saline-injected group (0[0-1], 5747Â1155; 0.7Â0.2; 0.3Â0.1) or the drugs injected alone (5-FU: Intestinal damage (2.5[2-3]), MPO [3788Â1212], TNF-α [0.7Â0.2], IL-6 [0.2Â2.3]; IRI: Intestinal damage (1[0-2]), MPO [3580Â1613], TNF-α [0.4Â0,2], IL-6 [0.07Â0.05]) (p<0.05). Conclusion: We developed a new experimental model of IM induced by the combination of IRI+5-FU in mice, which opens perspective for a more appropriate knowledge concerning the pathogenesis of IM. |
publishDate |
2013 |
dc.date.issued.fl_str_mv |
2013-12-05 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
status_str |
publishedVersion |
format |
masterThesis |
dc.identifier.uri.fl_str_mv |
http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=11712 |
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http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=11712 |
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por |
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por |
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info:eu-repo/semantics/openAccess |
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openAccess |
dc.format.none.fl_str_mv |
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dc.publisher.none.fl_str_mv |
Universidade Federal do Cearà |
dc.publisher.program.fl_str_mv |
Programa de PÃs-GraduaÃÃo em Farmacologia |
dc.publisher.initials.fl_str_mv |
UFC |
dc.publisher.country.fl_str_mv |
BR |
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Universidade Federal do Cearà |
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reponame:Biblioteca Digital de Teses e Dissertações da UFC instname:Universidade Federal do Ceará instacron:UFC |
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Biblioteca Digital de Teses e Dissertações da UFC |
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Biblioteca Digital de Teses e Dissertações da UFC |
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Universidade Federal do Ceará |
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UFC |
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mail@mail.com |
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