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1
Amaral, Catia Lira do. "Efeito do resveratrol na nefrotoxicidade induzida pela cisplatina em ratos." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/60/60134/tde-22052007-090133/.
Abstract:
O resveratrol (Res), um polifenol presente no vinho tinto, é conhecido por possuir potente atividade antioxidante. O efeito do resveratrol (Res) frente à nefrotoxicidade do antineoplásico cisplatina (cDDP) foi avaliado em ratos neste estudo. Os animais foram tratados com Res (25 mg/Kg de peso copóreo, ip., dose única) 30 minutos antes da administração de cisplatina (5 mg/Kg de peso copóreo, ip., dose única) e foram sacrificados depois de 2 ou 5 dias do tratamento. Após 5 dias, o aumento da creatinina sérica, volume urinário e proteinúria, que são marcadores de alterações renais, apresentaram significativa redução (p < 0,05) com a administração de resveratrol. Os ratos tratados com cisplatina apresentaram necrose tubular aguda e maior marcação imuno-histoquímica para células ED1 e linfócitos T no córtex e medula externa renal. Estas alterações foram menos intensas nos animais tratados com resveratrol. Após 2 dias, a administração de cisplatina aos ratos induziu aumento na concentração de malonaldeído (MDA) e reduziu nos níveis de glutationa (GSH) no tecido renal, que não foram amenizadas pelo resveratrol. Os resultados desse estudo indicam que o tratamento com resveratrol atenuou as alterações renais funcionais, histológicas e imuno-histoquímicas induzidas pela cisplatina. O efeito protetor provavelmente está relacionado à diminuição de infiltrado de células inflamatórias no tecido renalResveratrol (Res), a polyphenolic present in red wine, is known to possess potent antioxidant properties. The ability of resveratrol to protect against the nephrotoxicity of the antineoplastic agent cisplatin (cDDP) was evaluated in rats. The animals were treated with Res (25 mg/Kg body weight, ip., single dose) 30 minutes before administration of cDDP (5 mg/Kg body weight, ip., single dose) and then, sacrificed in 2 or 5 days followed by the treatment. After 5 days with resveratrol administration, the enhanced serum creatinine levels, urinary volume and urinary protein, which are indicative of renal injury, shown a significant reduction (p < 0.05). The cisplatintreated rats presented a tubular cell necrosis and increase immunostaining for ED1 and T-lymphocytes in the renal cortex and outer medulla. Those alterations were less intense in animals treated with resveratrol. After 2 days, administration of cisplatin to rats induced a higher malondialdehyde levels (MDA), and reduction in glutathione (GSH) concentrations in kidney tissue that were not prevented by resveratrol. In this study, the results indicate that resveratrol treatment attenuated the functional, histological and immunohistochemical renal alterations induced by cisplatin. The protect effect is relatated to the decrease of cells infiltrated at kidney tissue.
2
Santos, Graciela Cristina dos [UNESP]. "Avaliação do efeito protetor do urucum e da bixina sobre a genotoxicidade induzida pelo antitumoral cisplatina em células da linhagem PC12." Universidade Estadual Paulista (UNESP), 2008. http://hdl.handle.net/11449/100973.
Abstract:
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santos_gc_dr_arafcf.pdf: 2386901 bytes, checksum: b46aa55b36f051a8683831df1b69f150 (MD5)Universidade Estadual Paulista (UNESP)
A neuropatia induzida por drogas quimioterápicas é uma complicação no tratamento do câncer e outras doenças por ser freqüentemente dolorosa e requerer a interrupção da terapia. O antitumoral cisplatina é comumente usado contra muitas formas de câncer há aproximadamente 40 anos. Entretanto, sua aplicação é associada a muitos efeitos tóxicos, como neurotoxicidade, nefrotoxicidade, perda da audição e vômitos. Estes efeitos adversos têm levado ao desenvolvimento de agentes específicos para amenizar a toxicidade do fármaco. Alguns estudos sugerem que a administração de antioxidantes é capaz de reduzir os danos e proteger os tecidos. Dessa forma, os carotenóides são mais uma opção a ser avaliada, pois são considerados eficazes agentes antioxidantes. O urucum é uma fonte natural de corantes vermelhos e além da bixina (fração lipossolúvel do extrato), estão presentes nas suas sementes, outros carotenóides, como a norbixina, o bcaroteno, a criptoxantina, a luteína e a zeaxantina. Neste estudo, foi avaliada a genotoxicidade e a antigenotoxicidade do urucum e da bixina sobre a toxicidade induzida pelo antitumoral cisplatina em culturas de células PC12. A citotoxicidade foi determinada pelo método do MTT, a frequência de danos cromossômicos pelo Teste do Micronúcleo e a extensão de danos primários ao DNA pelo Ensaio do Cometa. O urucum e a bixina foram avaliados preliminarmente quanto a sua genotoxicidade. O urucum nas concentrações 0,2, 0,5 e 1,0 mg/mL e a bixina nas concentrações 0,05, 0,08 e 0,10 mg/mL não foram citotóxicos e nem genotóxicos às células PC12. Assim, essas concentrações foram utilizadas nos experimentos para verificar a proteção do urucum e da bixina contra os danos induzidos pela cisplatina. Embora o efeito protetor do urucum e da bixina não tenha sido evidente nos resultados obtidos pelo Ensaio do Cometa, eles se mostraram...
The neuropathy induced by chemotherapeutic drugs is a complication in the treatment of cancer and other diseases, because it is often painful and requires discontinuation of the therapy. Cisplatin has been commonly used against many forms of cancer for approximately 40 years. However, its application is associated with many toxic effects such as neurotoxicity, nephrotoxicity, hearing loss and vomiting. These adverse effects have led to the development of specific agents to lessen the toxicity of the drug. Some studies have suggested that the administration of antioxidants is able to reduce the damage and protect the tissues. Thus, the carotenoids are one more option to be evaluated, because they are considered to be effective antioxidants. Annatto is a natural source of red dyes and pigments and in addition to bixin (liposoluble fraction of the extract), other carotenoids are present in its seeds, such as norbixin, B-carotene, cryptoxanthin, lutein and zeaxanthin. In the present study, the genotoxicity and antigenotoxicity of annatto and bixin on the cisplatin induced-toxicity in PC12 cell cultures was assessed. Cytotoxicity was determined by the MTT assay, chromosomal damage by the Micronucleus test and the extent of primary damage to the DNA by the Comet assay. Annatto and bixin were first assessed with respect to their genotoxicity. Annatto concentrations of 0.2, 0.5 and 1.0 mg/ml and bixin concentrations of 0.05, 0.08 and 0.10 mg/ml were neither cytotoxic nor genotoxic to the PC12 cells. Thus, these concentrations were used in experiments to verify the protective effect of annatto and bixin against damage induced by cisplatin. Although the protective effect of annatto and bixin was not evident in the results obtained by the Comet assay, effective inhibition of the chromosomal damage (Micronucleus test) induced by cisplatin was shown. Annatto and bixin protected... (Complete abstract click electronic access below)
3
Santos, Graciela Cristina dos. "Avaliação do efeito protetor do urucum e da bixina sobre a genotoxicidade induzida pelo antitumoral cisplatina em células da linhagem PC12 /." Araraquara : [s.n.], 2008. http://hdl.handle.net/11449/100973.
Abstract:
Resumo: A neuropatia induzida por drogas quimioterápicas é uma complicação no tratamento do câncer e outras doenças por ser freqüentemente dolorosa e requerer a interrupção da terapia. O antitumoral cisplatina é comumente usado contra muitas formas de câncer há aproximadamente 40 anos. Entretanto, sua aplicação é associada a muitos efeitos tóxicos, como neurotoxicidade, nefrotoxicidade, perda da audição e vômitos. Estes efeitos adversos têm levado ao desenvolvimento de agentes específicos para amenizar a toxicidade do fármaco. Alguns estudos sugerem que a administração de antioxidantes é capaz de reduzir os danos e proteger os tecidos. Dessa forma, os carotenóides são mais uma opção a ser avaliada, pois são considerados eficazes agentes antioxidantes. O urucum é uma fonte natural de corantes vermelhos e além da bixina (fração lipossolúvel do extrato), estão presentes nas suas sementes, outros carotenóides, como a norbixina, o bcaroteno, a criptoxantina, a luteína e a zeaxantina. Neste estudo, foi avaliada a genotoxicidade e a antigenotoxicidade do urucum e da bixina sobre a toxicidade induzida pelo antitumoral cisplatina em culturas de células PC12. A citotoxicidade foi determinada pelo método do MTT, a frequência de danos cromossômicos pelo Teste do Micronúcleo e a extensão de danos primários ao DNA pelo Ensaio do Cometa. O urucum e a bixina foram avaliados preliminarmente quanto a sua genotoxicidade. O urucum nas concentrações 0,2, 0,5 e 1,0 mg/mL e a bixina nas concentrações 0,05, 0,08 e 0,10 mg/mL não foram citotóxicos e nem genotóxicos às células PC12. Assim, essas concentrações foram utilizadas nos experimentos para verificar a proteção do urucum e da bixina contra os danos induzidos pela cisplatina. Embora o efeito protetor do urucum e da bixina não tenha sido evidente nos resultados obtidos pelo Ensaio do Cometa, eles se mostraram... (Resumo completo, clicar acesso eletrônico abaixo)Abstract: The neuropathy induced by chemotherapeutic drugs is a complication in the treatment of cancer and other diseases, because it is often painful and requires discontinuation of the therapy. Cisplatin has been commonly used against many forms of cancer for approximately 40 years. However, its application is associated with many toxic effects such as neurotoxicity, nephrotoxicity, hearing loss and vomiting. These adverse effects have led to the development of specific agents to lessen the toxicity of the drug. Some studies have suggested that the administration of antioxidants is able to reduce the damage and protect the tissues. Thus, the carotenoids are one more option to be evaluated, because they are considered to be effective antioxidants. Annatto is a natural source of red dyes and pigments and in addition to bixin (liposoluble fraction of the extract), other carotenoids are present in its seeds, such as norbixin, B-carotene, cryptoxanthin, lutein and zeaxanthin. In the present study, the genotoxicity and antigenotoxicity of annatto and bixin on the cisplatin induced-toxicity in PC12 cell cultures was assessed. Cytotoxicity was determined by the MTT assay, chromosomal damage by the Micronucleus test and the extent of primary damage to the DNA by the Comet assay. Annatto and bixin were first assessed with respect to their genotoxicity. Annatto concentrations of 0.2, 0.5 and 1.0 mg/ml and bixin concentrations of 0.05, 0.08 and 0.10 mg/ml were neither cytotoxic nor genotoxic to the PC12 cells. Thus, these concentrations were used in experiments to verify the protective effect of annatto and bixin against damage induced by cisplatin. Although the protective effect of annatto and bixin was not evident in the results obtained by the Comet assay, effective inhibition of the chromosomal damage (Micronucleus test) induced by cisplatin was shown. Annatto and bixin protected... (Complete abstract click electronic access below)
Orientador: Maria de Lourdes Pires Bianchi
Coorientador: Antonio Cardozo dos Santos
Banca: Alessandro de Oliveira Rios
Banca: Daisy Maria Fávero Salvadori
Banca: João Bosco Faria
Banca: Cecilia Rodrigues Silva
Doutor
4
Kullmann, Maximilian [Verfasser]. "Identifying intracellular cisplatin interaction partners and assessing their contribution to cisplatin resistance / Maximilian Kullmann." Bonn : Universitäts- und Landesbibliothek Bonn, 2016. http://d-nb.info/111988876X/34.
5
Hadi, Sutopo. "The chemistry of cisplatin metabolites /." [St. Lucia, Qld.], 2007. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19800.pdf.
6
Zhang, Jin-Gang. "Cisplatin nephrotoxicity : mechanisms and antidotes." Thesis, University of Liverpool, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307635.
7
Castro, João Humberto Teotônio de [UNESP]. "Avaliação do espermograma de cães submetidos à administração de cisplatina." Universidade Estadual Paulista (UNESP), 2007. http://hdl.handle.net/11449/89030.
Abstract:
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castro_jht_me_jabo.pdf: 401295 bytes, checksum: 5932eead976a77a78dee0fb6c3fb9169 (MD5)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A correta orientação do Médico Veterinário, aos proprietários de cães, usados com finalidades reprodutivas, submetidas à quimioterapia com cisplatina, é importante na medida que este agente citostático age nas células em constante divisão, podendo ser citotóxicos para as células germinativas testiculares. O objetivo desse trabalho foi avaliar a qualidade espermática através do espermograma de cães que receberam cisplatina em diferentes momentos de análise espermática. A dose utilizada foi de 70 mg/mø, em intervalos de 21 dias, totalizando 4 infusões. Os cães foram divididos em dois grupos de 4 animais cada, sendo que um dos grupos recebeu a quimioterapia e o protocolo de diurese para proteção renal, já o grupo controle não recebeu a cisplatina, estando sujeito apenas aos fatores ambientais. Os resultados obtidos demonstraram que a cisplatina influenciou na qualidade espermática de cães, pois elevou as patologias maiores e totais acima do aceitável para cães aptos a reprodução. Portanto, infere-se que este citostático possa acarretar alterações morfofuncionais nos túbulos seminíferos e conduto epididimário.
The correct veterinary`s orientation for male dogs` owners used for reproduction goals, undergone cisplatin administration, is important because of this cistostatic act in cell with frequently proliferation, and could to cause germ cell injury. The objections of this experiment was to analysis the sperm quality through dogs` spermogram that received cisplatin`s infusions. The dose used was 70 mg/mø in 21 days periods, with 4 infusion in total. The dogs were divided in 2 groups with 4 animal each one. One of the groups received all the diuresys protocol (to protect the kidney) and the citostatic. And the other control group just didn`t receive the cisplatin infusion to know the real action of cisplatin effects without environmental stresses. The results show that cisplatin influence at the sperm quality in the dogs, because it elevated the major and total defects above that would be acceptable for competent dog to reproduct. It could deduct that cisplatin cause phisiologic alteration in the testis and epididymis.
8
Oliva, Carlos Alfredo Calpa [UNESP]. "Hemograma e teores séricos de Na, K, Mg, Ca e P de cães hígidos submetidos à administração de cisplatina." Universidade Estadual Paulista (UNESP), 2007. http://hdl.handle.net/11449/89087.
Abstract:
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oliva_cac_me_jabo.pdf: 178983 bytes, checksum: f310a85e1eb63818fa51dba6cafeadd8 (MD5)A cisplatina é um fármaco antineoplásico utilizado como adjuvante no tratamento de diversas neoplasias. Neste estudo foram avaliados o hemograma e os teores de sódio, potássio, magnésio, cálcio e fósforo do soro sanguíneo de cães submetidos à terapia com cisplatina. Foram utilizados oito cães, machos, sem raça definida, com 10 a 15 kg de peso, clinicamente sadios. Os cães foram distribuídos em dois grupos, contendo 4 animais cada, sendo que os animais do grupo 1 receberam cisplatina e aqueles do grupo 2 não receberam cisplatina. Os cães do grupo 1 receberam quimioterapia e protocolo de diurese para proteção renal, já o grupo controle 2 não recebeu a cisplatina, estando sujeito apenas aos fatores ambientais. Os animais do grupo 1 foram submetidos a quatro sessões de quimioterapia com cisplatina na dose de 70mg/mø, administrada por via intravenosa, durante 20 minutos, no intervalo de 21 dias. Antes da administração da cisplatina, realizou-se fluidoterapia com solução fisiológica a 0,9% na dose de 25mL/kg/hora, por via intravenosa, durante duas horas, e depois por mais uma hora. Todos os animais receberam metoclopramida na dose de 2mg/kg, por via intravenosa, 15 minutos antes da administração da cisplatina e furosemida na dose de 2 mg/kg, por via intravenosa, 5 minutos após administração de metoclopramida. As amostras foram processadas e analisadas antes de cada sessão de quimioterapia. Os resultados mostraram que não houve diferença significativa entre os grupos para as contagens de hemácias, concentração de hemoglobina, hematócrito e contagem de leucócitos, mesmo assim as concentrações séricas de eletrólitos mantiveram-se dentro dos padrões da normalidade. Os resultados obtidos podem ser indicativos de que o protocolo empregado para o grupo 1 se mostrou efetivo para manter as características do hemograma e a concentração sérica dos eletrólitos.
The cisplatin is an antineoplasic drug used like adjunct treatment of various neoplasms. In this study, one evaluated the hemogram and sodium, potassium, magnesium, calcium and phosphorus levels in the dogs` blood under administration of cisplatin. One used 8 male dogs, with no definite race, weighing from 10 to 15 kilograms, and clinically healthy. The dogs were divided into two groups of 4 animals each, being group 1 treated with cisplatin and group 2 with no cisplatin. Group 1 received chemotherapy and the diurese protocol for kidney protection, group 2 did not receive cisplatin, being exposed only to the environmental factors. The animals from group 1 were submitted to four chemotherapy sessions with cisplatin 70mg/m2 administered intravenously for 20 minutes, in a 21 days interval before the cisplatin administration, one carried out a fluidotherapy with physiologic solution 0,9% on a dosage of 25mg/kg/hour intravenously during 2 hours, and posteriorly for one more hour. All the animals received methoclopramid intravenously on a dosage of 2mg/kg, 15 minutes before the cisplatin and furosemide administration on a 2mg/kg dosage, 5 minutes before the cisplatin infusion. The evaluation of the hemogram and the electrolytes levels above mentioned were done before each chemotherapy session. The results demonstrate that there were no significant differences among the groups for red blood cells counting, hemoglobin concentration, hematocrit and leucocytes counting, but still, the electrolytes seric concentration maintained itself in a normal standard. The results obtained may indicate that the protocol employed for group 1 showed efficiency to maintain the characteristics of the hemogram and the electrolytes seric concentration.
9
Li, Yan Julia. "Cisplatin-induced cytotoxicity in MDCK cells." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6408.
Abstract:
Background. The mechanism of cisplatin-induced nephrotoxicity is not well understood. The distal tubules are affected in both human and animal studies, although the majority of cisplatin-induced renal damage is in proximal tubules. Platinum (Pt) forms intra- and interstrand cross-links with DNA in cancer cells. Hypothesis. A mechanism of cisplatin-induced cytotoxicity in MDCK cells relates to its ability to bind to DNA and interfere with its synthesis. Methods. The canine distal renal tubular epithelial cell line, MDCK was used as an in vitro model to investigate the mechanism of cisplatin-induced nephrotoxicity. The intracellular Pt accumulation and Pt binding with DNA were assayed by atomic absorption spectrophotometry. DNA synthesis was measured by BrdU labeling and fluorescence microscopy at the concentrations from 0 to 100 muM. The alkaline comet assay with 10 Gy radiation was used to measure Pt DNA interstrand cross-links after a one hour cisplatin exposure from 0 to 100 muM at both zero and sixteen hour time points. According to the principles of alkaline comet assay, the tail moment is inversely related with the amount of Pt interstrand cross-links. (Abstract shortened by UMI.)
10
Brock, Penelope. "Cisplatin toxicity in infants and children /." Leuven : Leuven University Press, 1994. http://www.gbv.de/dms/bs/toc/190814756.pdf.
11
Holding, Jeremy David. "Cisplatin : protein binding and biological activity." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257185.
12
Verma, Chandra Shekhar. "Modelling interactions between cisplatin and DNA." Thesis, University of York, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238705.
13
Baghai, Tabassom. "ATF3 as a Key Regulator of Cisplatin Cytotoxicity: Combining ATF3 Inducing Agents Enhances Cisplatin Activity in NSCLC." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37963.
Abstract:
Lung cancer is the leading cause of cancer and cancer deaths worldwide, with non-small-cell lung carcinomas (NSCLC) representing 85% of all diagnosed lung cancers. Platinum-combination chemotherapy is the current standard treatment for NSCLC, however, associated toxicities and resistance limit its efficacy. Our laboratory previously identified activating transcription factor 3 (ATF3), a stress-inducible gene whose elevated and sustained expression can trigger apoptosis to a wide variety of stressors, as a key regulator of cisplatin cytotoxicity as well. Thus, enhanced and sustained induction of ATF3 by combining platins with other ATF3 inducers potentially represents an effective therapeutic strategy. A chemical library screen identified vorinostat and topotecan as ATF3 inducers that also enhance cisplatin cytotoxicity. ATF3 plays a significant role in cisplatin, vorinostat and topotecan and their combinations cytotoxicity. Importantly, vorinostat and topotecan induced synergistic cytotoxicity with cisplatin in NSCLC cell lines and their cisplatin resistance sub-lines with enhanced ATF3 expression observed. Our study suggests a potential novel therapeutic approach where ATF3 inducing agents in combination with platins represents a rational combination based therapeutic strategy.
14
Romão, Marina Isabel Mendes. "Simulação de um modelo farmacocinético para a cisplatina." Master's thesis, [s.n.], 2012. http://hdl.handle.net/10284/3561.
Abstract:
Trabalho apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasA cisplatina é um dos fármacos mais utilizadas para tratar o cancro. A sua farmacocinética tem sido descrita por diversos modelos de compartimentos e de base fisiológica. Neste trabalho procurou demonstrar-se como o Excel© pode ser utilizado para simular o modelo mais utilizado para modelar a farmacocinética da cisplatina. A simulação em Excel© permitiu seguir a evolução temporal das concentrações de cisplatina e seus metabolitos em todos os tecidos do modelo, nomeadamente: plasma, fígado, rim, pele, sistema gastrointestinal e músculo. Os resultados da simulação são concordantes com os obtidos por Evans et al. para o mesmo modelo, com desvios da ordem dos 18 % quando se emprega o método de Euler para integrar o sistema de equações diferenciais. Cisplatin is widely used drug to treat cancer. Its pharmacokinetics has been described by many different compartment and physiological based models. In this work we demonstrated how Excel® can be used to simulate even the most complex pharmacokinetic models used to study the behavior of cisplatin in the human body. The simulation in Excel® allowed the time evolution of cisplatin and its metabolites in all tissues of the model namely: plasma, liver, kidney, skin, muscle and gastrointestinal system, to be followed. The simulation results are consistent with those obtained by Evans et al. for the same model, with deviations inferior to 18 % when employing the Euler method to integrate the system of differential equations.
15
OLIVETTO, Elena. "IPOACUSIA NEUROSENSORIALE E DANNO ISCHEMICO. MESSA A PUNTO DI UN MODELLO ANIMALE PER VALUTARNE GLI EFFETTI VASCOLARI E OSSIDATIVI." Doctoral thesis, Università degli studi di Ferrara, 2013. http://hdl.handle.net/11392/2388913.
Abstract:
Hearing impairment is an increasingly common disease. In Italy deaf people are about
seven million, including half a million adults with disabling hearing loss and over one
thousand births per year with congenital deafness. This causes difficulty in integration in
society for adults and prevents the language acquisition for children (Fekete, 1999).
As hearing loss has high social costs, the expectation for the development of new
treatments is extensive and diseases leading to hearing damage are increasingly studied
from clinic and base research. Hearing loss (HL) can have genetic causes, can be associated
with aging or exposure to noise or ototoxic substances, and the aetiology can be attributed
to vascular injury, trauma, tumours, infections or autoimmune response. All of these factors
could be ascribed to alterations in cochlear microcirculation resulting in hypoxia. This
condition can damage cochlear hair cells and neurons possibly leading to HL. Hypoxia and
ischemia can then be identified as possible factors contributing to the aetiology of
deafness, but they have not been experimentally studied yet.
The purpose of this work is to develop animal models of ischemia and infarction suitable for
the study of cochlear vascular damage, and to characterize them with electrophysiology
and gene/protein expression analyses. For this reason it was decided to monitor the effects
of ischemia in thrombosis mimicked by complete temporary carotid occlusion, and in stroke
mimicked by incomplete permanent left coronary artery. In particular this study focused on
the analysis of: organ of Corti and spiral ganglion structures, coagulation, oxidative stress
and apoptosis.
A further aim was to compare these models with other models of ototoxic damage, such as
noise and cisplatin. These models are both characterized for electrophysiology, oxidative
stress and apoptosis, but the possible involvement of vascular damage has not been
investigated yet. This comparison helped us to characterize the new models of vascular
injury in the oxidation and apoptosis expression patterns.
In our models, both infarction and ischemia cause a small but significant hearing loss,
localized at the cochlear apex. Furthermore, there is a slight induction of the coagulation
cascade, both in procoagulant and anticoagulant part, and an activation of JNK, that may
lead to cell survival. In addition, only in the carotid ischemia the cuticular plate of outer hair
cells is damaged.
Even noise and cisplatin cause vascular damage, but while in noise-treated animals the
coagulation genes show only an mRNA expression increase, after cisplatin administration
an mRNA and protein increase of the tissue factor is detected, which leads to the
coagulation cascade activation. In the ischemic models we did not detect any apoptosis
activation, while in the other models we noticed opposite reactions: in noise there is an
increased transcription of the anti-apoptotic genes that leads to cell survival, while cisplatin
activates pro-apoptotic factors. The activation of apoptosis is documented in literature and
is confirmed in both conditions by OHC loss detected in histological sections, which leads to
a more severe deafness than in the ischemia models.
In conclusion, the two models of ischemia developed are suitable for the study of cochlear
vascular damage, as they produce a slight hearing loss and give modifications in
coagulative, oxidative and apoptotic factors gene expression. Furthermore, the comparison
with two other widely used models allowed us to specify the pathways involved.
We can therefore say that all types of damage taken into consideration act on the inner ear
with vascular damage and oxidative mechanisms.
16
Singh, Tanya N. "Ru(II) complexes as photoactivated cisplatin analogs." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1150391177.
17
Dolling, Jo-Anna. "Cellular responses to ionizing radiation and cisplatin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ28336.pdf.
18
Ekborn, Andreas. "Cisplatin induced ototoxicity : pharmacokinetics, prediction and prevention /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-721-5.
19
Pussegoda, Kusala. "The pharmacogenomics of cisplatin-induced hearing loss." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42203.
Abstract:
Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumours. A serious complication of cisplatin treatment is permanent hearing loss. The study hypothesis is that genetic variants in genes involved in drug metabolism and transport can contribute to increased susceptibility to hearing loss in pediatric oncology patients treated with cisplatin. Patients were recruited from across Canada through the Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Recently, our group identified several predictive genetic variants that were highly associated with cisplatin-induced hearing loss in children. We evaluated whether we could replicate these findings in a new independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P=0.0013, Odds Ratio, OR 6.1) and ABCC3 (rs1051640, P=0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3 and COMT with clinical variables significantly improved the prediction of risk of developing hearing loss compared to clinical risk factors alone (P=0.00048). We next evaluated whether we could identify additional genetic variants that confer susceptibility to cisplatin-induced hearing loss. We identified novel variants in ABCB5 (rs10950831, P=1.06×10⁻⁶, OR 2.0) and DPYD (rs6667550, P=0.0047, OR 1.9) that were significantly associated with cisplatin-induced hearing loss. We included these variants into the initial genetic model that consists of variants in TPMT, ABCC3 and COMT to evaluate whether we could improve the prediction of risk. We demonstrate that the risk of prediction of hearing loss significantly improves by including genetic variants in ABCB5 and DPYD (P=0.0023). We also demonstrate that by combining the clinical and genetic factors we can significantly improve the prediction of risk of hearing loss compared to clinical factors alone (P=2.63x10⁻⁷). We were able to replicate previously described findings and also provide evidence for novel genetic variants in the prediction of cisplatin-induced hearing loss in children. Furthermore, this study demonstrates that predictive models can classify patients based on predicted risk of cisplatin-induced hearing loss. These findings have the potential to influence treatment modifications for cisplatin therapy and may improve safety in children.
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Mantzavinou, Aikaterini. "Sustained-release implants for intraperitoneal cisplatin delivery." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/120884.
Abstract:
Thesis: Ph. D. in Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2018.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 217-226).
The objective of this work was to develop materials for continuous low-dose delivery of cisplatin directly into the abdomen, also known as intraperitoneal (IP) chemotherapy. IP chemotherapy can help treat peritoneal metastasis in many advanced gynecologic and gastrointestinal cancers and has shown particular promise in treating advanced ovarian cancer. It is however tremendously underutilized because it requires a lot of resources and the current technology and maximum tolerated dose regimen cause complications and severe toxicity to patients. We previously showed that continuous low-dose IP cisplatin delivery via an implanted diffusion-based reservoir device can be as effective as and less toxic than intermittent maximum tolerated dose IP injections. To translate this work to a clinically relevant implantable system, we developed composite materials that can deliver cisplatin at a continuous low dose that is tunable. The materials were mechanically well suited for placement in the abdomen and were evaluated for in vitro bioactivity, in vivo tolerability and in vivo ability to deliver platinum to key abdominal organs with promising results. Dosing studies with different material dimensions helped identify a dose to pilot treatment of ovarian cancer in human xenograft-bearing mice. The implications of more accessible and affordable IP chemotherapy are especially important in countries with limited resources. Design reviews and a clinician survey in India reveal eagerness for early adoption of new technologies and dosing regimens to treat peritoneal metastasis and show promise for utilization of our implant in the developing world. The work described in this thesis carries implications for the treatment of advanced ovarian cancer and peritoneal metastasis of other tumors affecting millions of patients worldwide and may help with the management of nonmalignant conditions with abdominal involvement.
by Aikaterini Mantzavinou.
Ph. D. in Medical Engineering
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Barnes, Katie R. 1978. "Mechanism-based rational design of cisplatin analogues." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33647.
Abstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.Vita.
Includes bibliographical references.
The success of cisplatin as an anticancer drug is attributed to the ability of the platinum compound to damage DNA and subsequently induce apoptosis. Details of the cellular processing of cisplatin-damaged DNA can provide invaluable insight into the rational design of cisplatin analogues or combination therapies. Chapter I provides a survey of recent developments in the understanding of the mechanism of cisplatin action and summarizes relevant platinum-based anticancer compounds. Chapter 2 describes a series of estrogen-tethered platinum(IV) complexes (BEPn, n=l -5) that were synthesized, evaluated for their ability to upregulate HMGB1 and screened for cytotoxicity against human breast cancer cell lines. All BEPn complexes induced the overexpression of HMGB I in ER(+) MCF-7 cells. BEP3 was nearly twice as cytotoxic in ER(+) MC'F-7 cells than in ER(-) HCC-1937 cells. This result suggests the possibility of using compounds in this class specifically to target ER(+) malignancies, such as breast and ovarian cancers. In addition, the series of BEPn compounds provide an example of a useful strategy in the development of platinum-containing anticancer agents, namely, using mechanistic insights to aid in the rational design of new complexes.
(cont.) The strategy of exploiting estrogen-induced HMGBI upregulation to sensitize ER(+) cells to platinum was further pursued in work described in chapters 3 and 4. Chapter 3 reports the synthesis and characterization of a series of platinum(IV)-estrogen conjugates derived from carboplatin. Although these BECPn complexes were moderately cytotoxic in ER(+) MCF-7 human breast cancer cells, no differential cytotoxicity was observed as compared to ER(-) HCC- 1937 cells. However, these compounds represent the first example of a biomolecule-tethered platinum(IV) complex that reduces to yield carboplatin in cells. The platinum estrogen conjugate described in chapter 4 was designed not only to induce upregulation of HMGB I but also to enter ER(+) cells selectively. Unlike the BEP and BECP compounds, BEEP was designed to maintain affinity for the estrogen receptor and by tethering platinum to estradiol through the 17c-position of the steroid ring. Compounds with affinity for the estrogen receptor, which is overexpressed in breast and ovarian cancers, are selectively taken up into ER(+) cells. Unexpectedly, BEEP had very low affinity for the estrogen receptor and was therefore equally cytotoxic in ER(+) and ER(-) human breast cancer cell lines.
(cont.) A common feature of many cancers is overexpression of the folate receptor, which is responsible for the uptake of folic acid. Therefore targeting the folic receptor is an attractive method for achieving selective uptake in cancer cells. Chapter 5 describes the synthesis and biological activity of a folic acid-tethered platinum(lV) compound, which demonstrates the validity of this premise. The nuclear protein HMGBI has recently been discovered to function as an extracellular signaling agent. Because of oxygen deprivation, the core of a solid tumor dies by necrosis and passively releases HMGB I into the extracellular environment. This characteristic of solid tumors leads to the hypothesis that extracellular HMGB I is taken up by surrounding viable tumor tissue and mediates cisplatin sensitivity. The final chapter investigates the capability of exogenously administered HMGB to modulate the cytotoxicity of cisplatin and trans-DDP in human cancer cells. The Appendix sections provide detailed experimental protocols for several useful laboratory methods. In Appendix A, a procedure for isolation of nuclei from cisplatin-treated cells is presented.
(cont.) The nuclei were subsequently used by our collaborators to examine the post- translational modifications of histones induced by cisplatin exposure. A protocol for isolation of protein extracts from formalin-fixed paraffin-embedded tissue is described in Appendix B. In addition, the extracts were probed by western blot analysis to examine the expression levels of HMGB1 in clinical testicular seminoma samples. Appendix C provides a solid-phase synthetic methodology for the preparation of peptide-conjugated platinum(IV) compounds.
by Katie R. Barnes.
Ph.D.
22
Bhatta, Puspanjali. "Protective effect of capsaicin against cisplatin ototoxicity." OpenSIUC, 2014. https://opensiuc.lib.siu.edu/theses/1579.
Abstract:
Cisplatin is a widely used chemotherapeutic drug for the treatment of solid tumors. However, the drug accumulates in the cochlea, and damages inner ear structures, resulting in bilateral andpermanent hearing loss. Previous data from our laboratory indicate that activation of the transient receptor potential vanilloid 1 (TRPV1) receptor (by capsaicin) increases the NOX3 isoform of NADPH oxidase, leading to the generation of reactive oxygen species (ROS) in the cochlea, transient cochlear inflammation and transient hearing loss. We also demonstrated that the transient inflammation was produced by ROS-mediated activation of signal transducer and activator of transcription 1 (STAT1). Surprisingly, over time, this response desensitizes and capsaicin was subsequently able to protect against cisplatin ototoxicity. The goal of this study was to determine the mechanism of otoprotection against cisplatin ototoxicity following the administration of capsaicin. For this study we utilize both an immortalized organ of Corti outer hair cells and rat cochlea. Capsaicin (2.5 µM) increased both Ser727 p-STAT1 and Tyr705 p-STAT3 implicating its role in inflammation. Expression of cannabinoid receptors were observed in UB/OC-1 cells as well as rat outer hair cells (OHCs). However, inhibition of CB2 receptors (by AM630) reduced capsaicin-mediated Tyr705 p-STAT3, but had little effect on Ser727 STAT1. Capsaicin protected UB/OC-1 cells against cisplatin-induced apoptosis. This protection was reversed by CB2 antagonist but potentiated by TRPV1 inhibition. Significant cell death was observed following treatment of UB/OC-1 cells with AM630 alone, underscoring the importance of CB2 receptors in survival of these cells. CB2 agonist, JWH, significantly increased the protective signal, STAT3. Furthermore, capsaicin-mediated protection was reversed by the inhibition of STAT3, implicating STAT3 in otoprotection. In animal studies, oral administration of capsaicin (0.5% solution) induced transient inflammation but led to a long term recovery. Animals pre-treated with oral capsaicin were protected against cisplatin-induced hearing loss as compared to vehicle-treated animals, suggesting protection against hearing loss. Capsaicin increased the expression of both CB1 and CB2 receptors in the organ of Corti, which might confer the long term protective actions of this agent against hearing loss. In rats pretreated with AM630, the protective action of capsaicin was abolished. We conclude that otoprotection mediated by capsaicin is produced by activation of CB receptors in the cochlea which are coupled to both STAT1 and STAT3 activation. However, our data support the conclusion that activation of STAT3 confers the otoprotective action of capsaicin. In contrast, activation of STAT1 by capsaicin could contribute to the transient inflammatory response previously observed in vivo. The net protective action of capsaicin could result from an increase in the STAT3/STAT1 ratio of cells in the cochlea, which antagonizes the ability of cisplatin lower this ratio and promote cell death.
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Dantas, Marcos Vinicius Mendes. "Influência do quimioterápico Cisplatina sobre o reparo e mineralização ao redor de implantes dentários e sobre a qualidade do tecido ósseo : estudo mecânico e histométrico in vivo /." Araraquara, 2018. http://hdl.handle.net/11449/154089.
Abstract:
Orientador: Marisa Aparecida Cabrini GabrielliResumo: A maioria dos pacientes submetidos a tratamentos de câncer bucal são impossibilitados de receber reabilitação com próteses dentais convencionais. Assim, a confecção de próteses suportadas por implantes dentários osseointegráveis tem sido considerada uma alternativa. Apesar dos elevados índices de sucesso destes tratamentos, pode haver um inconveniente em se reabilitar esses pacientes. Alguns quimioterápicos, como a Cisplatina, apresentam efeitos colaterais como redução na remodelação óssea e/ou alteração na nutrição desse tecido, o que pode interferir com a osseointegração dos implantes. O presente estudo avaliou, em ratos, o efeito da terapia em longo prazo com Cisplatina sobre o processo de reparo e mineralização óssea ao redor de implantes e sobre as propriedades mecânicas do tecido ósseo. Para isso, 43 ratos foram distribuídos aleatoriamente em 2 grupos: cisplatina (CIS, n=23), no qual os animais receberam administração intraperitoneal de cisplatina uma vez a cada semana durante 4 semanas, totalizando 4 administrações, e controle (CTL, n=20), no qual os animais receberam administração a cada 1 semana de placebo, durante todo o período experimental. Após 28 dias do início do tratamento, um implante de titânio foi instalado na metáfise tibial, em ambas as pernas. Os animais foram sacrificados 30 e 60 dias após a instalação dos implantes, sendo retirados os fêmures e as tíbias. Os fêmures foram submetidos aos testes mecânicos de força máxima (N), força de ruptura (N), força ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Most of patients undergoing oral cancer treatments are unable to receive rehabilitation with conventional dental prostheses. Thus, the use of prostheses supported by osseointegrated implants has been considered as an alternative. Despite the high rate of success of the dental treatments, there may be an inconvenience to rehabilitate these patients. Some chemotherapeutic agents as Cisplatin exhibit undesirable side effects, such as the reduction in bone remodeling and/or changes in nutrition of tissue, which can interfere with the osseointegration of implants. This study evaluated, in rats, the effect of the long-term therapy with Cisplatin on bone healing and mineralization around implants and on the mechanical properties of bone tissue. Forty-three rats were randomly divided into two groups: Cisplatin (CIS, n=23), in which the animals received subcutaneous administration of Cisplatin once a week for 4 weeks (a total of 4 administrations) and control (CTL, n=20), in which the animals received a placebo solution once a week throughout the trial period. After 28 days of treatment initiation, a titanium implant were installed in the tibial metaphysis, on both legs. The animals from each group were sacrificed 30 and 60 days after the implant placement, and their femurs and tibias removed. Femurs were subjected to mechanical tests of maximum strength (N), maximum rupture force (N), maximum strength (mm), and rupture (mm). The tibias with the implants were assessed for removal torq... (Complete abstract click electronic access below)
Doutor
24
Gonçalves, Estela Maria. "Efeito da cisplatina em cultura de linhagens estabelecidas e sua capacidade de induzir transformação celular in vitro." [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317944.
Abstract:
Orientador: Selma Candelaria GenariTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-05T19:22:08Z (GMT). No. of bitstreams: 1 Goncalves_EstelaMaria_D.pdf: 4512893 bytes, checksum: 36b5b4604b23f405a7254a71f5971cd4 (MD5) Previous issue date: 2005
Resumo: A cisplatina é um agente antineoplásico utilizado no tratamento quimioterápico de tumores como os de testículo, de ovário e de bexiga urinária. Contudo, estudos indicam que a cisplatina apresenta potencial mutagênico, genotóxico e tumorigênico tanto in vitro como in vivo. Após tratamento com 50 µg/ml de cisplatina durante 24 h, células Vero apresentaram alterações comportamentais e morfológicas associadas à transformação celular in vitro. Modificações morfológicas foram investigadas com utilização de imunocitoquímica (fibronectina), microscopia eletrônica de varredura e coloração faloidina-fluoresceína (actina). O estudo proliferativo foi realizado a partir de curvas de crescimento e o padrão de adesão celular foi obtido através de testes de adesão. Características citogenéticas foram avaliadas em células Vero e V79 tratadas com cisplatina, através da determinação dos números modais de cromossomos, das freqüências de poliploidia e dos índices mitóticos. Células Vero controles apresentaram crescimento em monocamadas, enquanto que células Vero transformadas cresceram em múltiplas camadas, formando grumos ou agregados celulares. A proliferação celular e as características morfológicas e de adesão das células Vero transformadas foram acentuadamente diferentes das células controles. Células Vero transformadas e células V79 tratadas com cisplatina apresentaram alterações nos números de cromossomos além de aumento nos índices mitóticos e nas freqüências de poliploidia. Os resultados obtidos indicam que as alterações morfológicas, de crescimento e de adesão observadas em células Vero e as alterações citogenéticas, observadas em células Vero e em células V79, provavelmente relacionam-se com a transformação celular in vitro induzida pelo tratamento com cisplatina. Estas células Vero transformadas apresentam características associadas ao crescimento neoplásico, podendo ser utilizadas como modelo de estudo de células tumorais in vitro
Abstract: Cisplatin is an antineoplastic agent used to treat solid malignancies, such as testicular, ovarian and bladder tumors. However, both in vitro and in vivo, cisplatin has been shown to be mutagenic, genotoxic and tumorigenic. Maintained in culture, Vero cells presented behavioral and morphological alterations associated with cellular transformation in vitro, after treatment with 50 µg/ml of cisplatin during 24 h. The morphological alterations were investigated using immunocytochemistry (fibronectin), scanning electron microscopy and the actin cytoskeleton was labeling with fluorescein isothiocyanate-phalloidin. The study of proliferation was obtained from the growth curve and the adhesion pattern was obtained from the adhesion assay. In Vero and V79 cells treated with cisplatin, cytogenetical characteristics were obtained by modal chromosome numbers, polyploidy frequencies and mitotic index determinations. Control Vero cells presented growth in a monolayer, while the transformed cells grew in multilayers forming cellular aggregates. The cellular proliferation, adhesion pattern and morphological characteristics of the transformed Vero cells were very different from the control ones. Transformed Vero cells and cisplatin-treated V79 cells presented altered chromosome numbers. Polyploidy frequencies and mitotic indexes were also enhanced in these cells. The results indicate that morphological, growth and adhesion changes observed in Vero cells and cytogenetical alterations, observed in Vero and V79 cells, probably resulted from cellular transformation in vitro induced by cisplatin treatment. These transformed Vero cells presented characteristics associated with neoplastic growth, and can be used as a model for tumor cells studies in vitro
Doutorado
Biologia Celular
Doutor em Biologia Celular e Estrutural
25
Martins, Nádia Maria. "Avaliação do estresse oxidativo e estado redox mitocondrial na hepatotoxicidade induzida pela cisplatina em ratos \'Wistar\': efeito protetor da dimetiltiouréia." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/60/60134/tde-24072007-095608/.
Abstract:
A cisplatina ainda é um dos agentes quimioterápicos mais efetivos. No entanto, em elevadas doses pode ocorrer hepatotoxicidade. Alguns antioxidantes têm sido mostrado amenizar a hepatotoxicidade induzida pela cisplatina mas o mecanismo molecular envolvido não está bem esclarecido.No presente estudo nós investigamos moleculares subjacente ao efeito protetor da dimetiltiuouréia (DMTU), um conhecido eqüestrador de radical hidroxil, contra a lesão oxidativamitocondrial hepática induzida pela cisplatina em ratos. Ratos Wistar machos adultos ( 200 a 220g) foram divididos entre 4 grupos de 8 animais cada. O grupo controle foi tratado apenas com uma injeção intraperitoneal (i.p.) de solução salina (1 ml/ 100g de peso). Ao grupo DMTU foi administrado apenas DMTU (500 mg/kg de peso, i.p., seguido de 125 mg/kg, i.p., duas vezes ao dia até o sacrifício). Ao grupo cisplatina foi administrado uma injeção única de cisplatina (10 mg/kg de peso, i.p.). Ao grupo DMTU + cisplatina foi administrado DMTU (500mg/kg de peso, i.p.), pouco antes da injeção da cisplatina (10 mg/kg de peso, i.p.), seguido por injeções de DMTU (125 mg/kg de peso, i.p.) duas vezes ao dia até o sacrifício ( 72 horas após o tratamento). A hepatotoxicidade foi evidenciada no grupo cisplatina pelo aumento dos níveis séricos de alanina (ALT) e aspartato (AST)aminotransferases. O mecanismo de hepatotoxicidade induzido pela cisplatina mostrou-se envolvido na rigidez de membrana; na redução da razão glutationa reduzida em relação a glutationa oxidada (GSH/GSSG); na redução dos níveis de ATP, GSH e NADPH; na lipoperoxidação; na lesão oxidativa da cardiolipina e de proteínas com grupos fidrílicos. Mais ainda, a morte celular por apoptose foi também demonstrada e os achados fortemente sugerem a participação do xi mecanismo sinalizador mitocondrial neste processo; o DMTU não apresentou nenhum efeito direto sobre a mitocôndria e inibiu substancialmente a lesão mitocondrial induzida pela cisplatina, prevenindo a hepatotoxicidade. Todos os seguintes efeitos induzidos pela cisplatina foram previnidos pelo DMTU: (a) elevação dos níveis séricos de AST e ALT; (b) redução dos níveis de ATP hepático;(c)peroxidação lipídica;(d)oxidação da cardiolipina; (e)oxidação de proteínas sulfidrílicas; (f) rigidez da membrana mitocondrial; (g) oxidação de GSH; (h)oxidação de NADPH e (i) morte celular por apoptose. Os resultados mostraram o papel principal da mitocôndria e dos radicais hidroxilas na proteção do fígado saudável contra a lesão hepática induzida pela cisplatina, delineando um número de etapas que podem ser consideradas no desenvolvimento de futuros agentes citoprotetoresCisplatin is still one of the most effective chemotherapeutic agents. However, at higher doses hepatotoxicity may occur. Some antioxidants have been shown to ameliorate cisplatin-induced hepatotoxicity but the involved molecular mechanism has not been clarified. In the present study we investigated the molecular mechanism underlying the protective effect of dimethylthiourea (DMTU), a known hydroxyl radical scavenger, against liver mitochondrial oxidative damage induced by cisplatin in rats.Adult male Wistar rats (200 to 220g) were divided into 4 groups of 8 animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1ml/100g body weight). The DMTU group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until sacrifice). The cisplatin group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The DMTU+cisplatin group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until sacrifice (72 hours after the treatment). epatotoxicity was evidenced in the cisplatin group by the increased serum levels of alanine (ALT) and aspartate (AST) aminotransferases. The mechanism of cisplatininduced hepatotoxicity was found to involve membrane rigidification; decreased GSH/GSSG ratio, ATP, GSH and NADPH levels; lipid peroxidation; oxidative damage of cardiolipin and protein sulfhydryl groups. Moreover, cell death by apoptosis was also demonstrated and the findings strongly suggest the participation of the mitochondrial signaling pathway in this process; DMTU did not present any direct effect on mitochondria and substantially inhibited cisplatin-induced mitochondrial injury, therefore preventing the hepatotoxicity. All the following cisplatin-induced xiv effects were prevented by DMTU: (a) elevation of AST and ALT serum levels; (b) decreased hepatic ATP levels; (c) lipid peroxidation; (d)cardiolipin oxidation; (e) sulfhydryl protein oxidation; (f) mitochondrial membrane rigidification; (g) GSH oxidation; (h) NADPH oxidation and (h) apoptotic cell death. Results show the central role of mitochondria and hydroxyl radicals in the protection of healthy liver against cisplatin-induced injury, highlighting a number of steps that might be considered in the development of novel cytoprotective agents.
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Horáčková, Lucie. "Testování viability nádorových linií buněk po působení chemických látek a chemoterapeutik." Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2018. http://www.nusl.cz/ntk/nusl-376847.
Abstract:
Individual types of viability tests based on colorimetric changes of the solution are desribed in the theoretical part. Furthermore, HSP proteins are characterized, which are not connected only by heat shock, but also during other cell stresses such as exposure to UV, cold, extreme pH or heavy metals. They are important for the cell, because they help to reformulate proteins that have been damaged by cellular stress and also bind to new unpacked proteins and ensure their correct folding. Proteins that are affected by molecular chaperones are collectively called client proteins. Some HSPs also contribute to membrane transport or degradation. These proteins are co-operative with the cochaperones, which are important for heat shock proteins because they help them to pack protein, in particular by catalyzing the hydrolysis of ATP to ADP. Herein is also described cisplatin and its derivatives, including mechanism of action and adverse effects. This work was focused on detection cytotoxicity of cisplatin and its derivatives. Cells were exposed to stress condition induced by cytostatics and huge changes in heat shock proteins and cochaperon levels were observed. There was also observed colocalization of heat shock proteins and their client protein p53 by confocal microscopy in these stressing conditions.
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García, Rodríguez Francisco J. "Caenorhabditis elegans as animal model to investigate the cellular mechanism of resistance for the chemotherapeutic agent cisplatin." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/397787.
Abstract:
In the last three decades, cisplatin has been one of the most widely prescribed drugs being an effective treatment for many cancer types. Despite its effectiveness, many patients are intrinsically resistant to cisplatin-based therapies and an important fraction of tumors eventually develop chemoresistance to this agent. In this study we consolidate C. elegans as a pluricellular model (I) to better understand the biological response to cisplatin-based chemotherapy to finally to map cellular pathways capable of modulating the response to cisplatin and (II) to functionally validate candidate genes involved in the such response to cisplatin.
We discover that cisplatin-induced damage provokes in worms specific cell-type apoptotic activation and induces a systemic response promoting the activation of a set of redox-stress responsive genes whose transcription is mediated by the evolutionary conserved Insulin-IGF-like receptor signaling pathway (IIS) transcription factors SKN-1/Nrf2 and DAF-16/FOXO. In addition, altering both IIS-pathway-related genes and some of their targets leads to modify the response to cisplatin. Accordingly, this study demonstrates the importance of redox homeostasis in the resistance to cisplatin, and the central role of Nrf2/SKN-1 and FOXO/DAF-16 as modulators of cisplatin resistance acquisition through this mechanism, which is conserved from worms to mammals.
We also demonstrated, after an RNAi based approach using C. elegans, that several genes present at the 9q32-q33.1 human region, such as the glucosyl ceramide synthase or the copper transporter, were able to individually alter the response to cisplatin. Moreover, we demonstrated the relevance of the glucosylceramide synthase activity as a biological mechanism that mediate tumor cell protection against cisplatin exposure in tumorgraft models, highlighting the relevance of targeting glucosylceramide synthase as a novel approach to resensitize tumors to cisplatin. This confirms the translational value of C. elegans in cisplatin-based research, which could fill the gap between in vitro and preclinical studies.El cisplatino ha sido uno de los agentes quimioterapeúticos más usados durante las últimas tres décadas, mostrandose útil en el tratamiento de diferentes tipos de cáncer. A pesar de esa efectividad, muchos tumores son resistentes al fármaco de forma intrínseca, así como otros son capaces de desarrollar resistencia frente a este agente. En este trabajo se busca consolidar al nemátodo Caenorhabditis elegans como modelo pluricelular en el estudio del cisplatino con el objetivo de (I) comprender la respuesta biológica frente a la quimioterapia basada en este agente, para así poder localizar nuevas vías celulares capaces de modular dicha respuesta frente a cisplatino y, por otra parte, (II) validar, de forma funcional, genes que posiblemente están involucrados en la respuesta a cisplatino. En este proyecto, hemos descubierto que el efecto producido por el cisplatino induce en estos gusanos una activación en la vía de señalización de la apoptosis que es específica de determinados tipos celulares. En paralelo, también provoca la activación de una batería de genes relacionados con la respuesta al estrés oxidativo, cuya transcripción es regulada por la vía de señalización de la Insulina/IGF-like receptor (IIS) a través de los factores de transcripción SKN-1/Nrf2 y DAF-16/FOXO. Esta vía está conservada a lo largo de la evolución y en este trabajo hemos demostrado que alterando la actividad de ambos factores de transcripción, o bien de alguno de sus genes efectores, es posible modificar la respuesta frente a cisplatino en gusanos. En relación, este estudio demuestra la importancia del mantenimiento del balance oxidativo en la resistencia al cisplatino, así como el papel central de Nrf2/SKN-1 y FOXO/DAF-16 como moduladores en la resistencia frente a cisplatino a través de este mecanismo, el cual esta conservado de gusanos a mamíferos. En este proyecto también se ha demostrado usando C. elegans, a través de ensayos basados en RNA de interferencia, que varios genes localizados en la región q32-q33.1 del cromosoma 9 humano, como la ceramida glucosiltransferasa o los transportadores de cobre, son capaces de alterar la respuesta a cisplatino de forma individual. Además, a través de ensayos usando tumores ortotópicos implantados en ratones, hemos demostrado la relevancia que tiene la actividad de uno de estos genes, la ceramida glucosiltransferasa, como mecanismo biológico capaz de proteger a las células tumorales frente al cisplatino. Esto confirma la importancia de la inactivación de esta enzima como un nuevo método para resensibilizar tumores resistentes frente a cisplatino, así como también confirma la capacidad translacional del uso de C. elegans como modelo animal en la investigación basada en cisplatino, lo cual podría rellenar el vacío existente entre los estudios in vitro y preclínicos.
28
Vernieux, Louise Winsome. "Cisplatin chemotherapy, the auditory verbal learning test, and the structure of memory /." [St. Lucia, Qld.], 1997. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17065.pdf.
29
Kong, Bao. "THE ROLE AND REGULATION of MITOCHONDRIAL DYNAMICS IN CISPLATIN RESISTANCE IN HUMAN GYNECOLOGIC CANCER CELLS." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32461.
Abstract:
Cervical cancer (CECA) and ovarian cancer (OVCA) rank first and third in the number of new cases diagnosed among gynecologic cancers，and chemoresistance severely limits their treatment success. The underlying mechanism of chemoresistance is multi-factorial and partly due to defects in drug-induced apoptosis. Cisplatinum (CDDP) -induced, p53-mediated mitochondrial cell death is controlled by Akt and is a determinant of chemosensitivity in gynecologic cancer cells. Mitochondria dynamics (fusion and fission) are involved in the regulation of mitochondria-mediated apoptosis. The tumor suppressor prohibitin 1 (Phb1) is involved in long from Opa1 (L-Opa1) processing and p53-regulated apoptosis. Whether mitochondrial fusion protein Opa1 and its protease Oma1 as well as Phb1 are involved in the regulation of chemoresistance in CECA and OVCA cells are not known.
The overall objective of my research is to increase the current understanding on the regulation of mitochondrial dynamics and on its role in chemoresistance in gynecologic cancer cells. We hypothesize that CDDP induces Phb1 binding to phosphorylated p53 (p-p53) and Bak, resulting in Bak activation and mitochondrial outer membrane permeabilization (MOMP). These responses also induce Oma1-mediated Opa1 processing, mitochondrial fragmentation and apoptosis but are inhibited by high Akt level in chemoresistant cells.
Here we present evidence that CDDP induces Oma1 activation, L-Opa1 processing and mitochondrial fragmentation in chemosensitive but not in chemoresistant cells. Silencing p53 expression attenuated CDDP-induced L-Opa1 loss, mitochondrial fragmentation and apoptosis in chemosensitive cells, while reconstitution of p53 in p53-deficient (mutant or null) chemoresistant cells induced Oma1 activation, L-Opa1 processing and changes in mitochondrial dynamics irrespective of the presence of CDDP. In response to CDDP, p-p53 (ser15) dissociates Phb1 from Opa1-Phb1 complex and binds to Bak in chemosensitive but not chemoresistant cells. Inhibition of Akt is required for CDDP to induce L-Opa1 processing, mitochondrial fragmentation and apoptosis in chemoresistant cells.
Our study suggests a mechanism that p53 regulates L-Opa1 processing and mitochondrial fragmentation in chemosensitive cells induced by CDDP, while this pathway is suppressed in chemoresistant cells. Dysregulated mitochondrial dynamics may in part be involved in the pathophysiology of CDDP resistance. Inhibiting Akt activity and inducing Opa1 processing may serve as novel therapeutic strategies for these gynecologic cancers.
30
DI, TELLA LUCIA. "Different p63 mediated response induced by doxorubicin and cisplatin: P63 activation by c-Abl in the cisplatin induced apoptotic pathway." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2008. http://hdl.handle.net/2108/579.
Abstract:
I membri della famiglia di p53 hanno funzioni simili e differenti. La proteina p53 è coinvolta nella risposta al danno al DNA provocando arresto del ciclo cellulare o apoptosi. Anche p73 induce arresto del ciclo cellulare o apoptosi dopo un danneggiamento del DNA. P63 è un membro della famiglia di p53 ma si conosce poco circa il suo ruolo nella risposta al danno al DNA e nel cancro.
TAp63α è espresso negli oociti ed è essenziale per provocare la morte degli oociti in seguito al danneggiamento del DNA senza coinvolgere p53. Il danno al DNA induce il legame di p63 alle sequenze di DNA riconosciute dai membri della famiglia di p53, come indicano esperimenti di oligonucleotidi biotinilati; questi eventi sembrano essere legati alla morte degli oociti.
In questa tesi noi vogliamo studiare il ruolo di p63 nella risposta al danno al DNA provocato da diverse sostanze chemioterapeutiche come doxorubicina e cisplatino.
Noi abbiamo dimostrato che la proteina p63 subisce delle modificazioni post-traduzionali in seguito all’uso di doxorubicina o cisplatino. Analizzando la corsa elettroforetica della proteina trattata con le sostanze chemoterapeutiche si nota che l’isoforma Tap63alfa mostra una riduzione nella corsa elettroforetica solo dopo aver somministrato inibitori della Topoisomerasi II (doxorubicina e etoposside), mentre in presenza di cisplatino la quantità di Tap63alfa appare significativamente aumentata.
TAp63 alfa transattiva geni apoptosis e induce apoptosi se trattata con cisplatino. Il trattamento con doxorubicina invece non innesca in alcun modo l’apoptosi.
In questa tesi noi analizziamo a livello molecolare la risposta di TAp63 provocata dal cisplatino. Nella linea germinale femminile (oociti) il danneggiamento del DNA provoca la fosforilazione di p63 (Suh, 2006). Tuttavia le chinasi coinvolte sono ancora sconosciute.
Noi abbiamo dimostrato che, in seguito al trattamento con cisplatino, TAp63 è fosforilata dalla chinasi c-Abl sulla tirosina 149 in una regione ricca di proline. Inoltre, attraverso la tecnica del silenziamento dell’RNA, abbiamo descritto che la abilità di p63 di transattivare geni apoptotici e la capacità di indurre apoptosi richiede la sua fosforilazioneda da c-Abl.P53 family members have distinct and overlapping functions. P53 is involved in DNA damage response inducing cell cycle arrest or apoptosis. Also p73 induce cell growth arrest and apoptotic pathway after DNA damage. P63 is a member of p53 family, but little is known about its role in DNA damage response and in the cancer. It has reported that TAp63α is expressed in female germ cells and is essential in a process of DNA damage-induced oocyte death not involving p53. DNA damage induces p63 binding to p53 cognate DNA sites as judged by DNA binding assay performed on biotinylated double- strand oligonucleotide, and that these events seem linked to oocyte death. In this thesis we focus on the p63 mediated response to DNA damage response induced by different chemotherapeutic agents such as doxorubicin and cisplatin. We demonstrated that p63 protein undergoes posttranslational modification upon doxorubicin and cisplatin exposure. TAp63alpha isoform shows the reduction in electrophoretic mobility only after topoisomerase II inhibitors (doxorubicin and etoposide), whereas in the presence of cisplatin the TAp63alpha protein level is significantly increased. TAp63alpha upregulates different genes after doxorubicin compared to the cisplatin treatment, indeed upon cisplatin exposure TAp63 transactivates apoptotic genes and induce apoptosis whereas p63 does not upregulate genes involved in apoptosis and does not induce apoptosis upon doxorubicin exposure. In this thesis we analyzed, at molecular level, the TAp63 response triggered by cisplatin. In female germ line it has been described that DNA damage is communicated to p63 through phosphorylation (Suh, 2006). However, the upstream kinases are yet unknown. Here we show that, upon cisplatin treatment, TAp63 is phosphorylated by the phosphotyrosine kinase c-Abl on the tyrosine 149 in the proline rich region. Moreover we show, by RNA interference technique, that the p63 mediated upregulation of the genes involved in apoptosis and the induction of apoptosis, required the TAp63alpha phosphorylation by c-Abl.
31
Bulmer, J. Todd. "Cellular responses to the anti-cancer drug, cisplatin /." *McMaster only, 2001.
32
Chu, Wendy. "Mechanism of cisplatin resistance in human malignant melanoma." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq45534.pdf.
33
Mandić, Aleksandra. "Elucidation of pro-apoptotic signaling induced by cisplatin /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-449-6.
34
Salehi, Dermanaki Pezhman. "Prevention of cisplatin ototoxicity by curcumin loaded nanoparticles." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121427.
Abstract:
Cisplatin is an effective chemotherapeutic agent which causes oxidative and inflammatory damages to the cochlea, the hearing organ of the auditory system. The degenerative changes of the cochlea as a result of cisplatin chemotherapy lead to permanent hearing loss in patients, especially in younger children. Curcumin is a phytochemical compound known to exert various biological properties including acting as an effective antioxidant agent. In this study, curcumin was encapsulated by NIPAAM/VP/PEG-A nanoparticles to increase the bioavailability of the drug. Our hypothesis is that a combination therapy of curcumin loaded nanoparticles and dexamethasone can reduce the cisplatin-induced oxidative and inflammatory stress to the hearing organ. In a first step, characterization of the curcumin nanoparticles showed moderate stability in aqueous matrix, and temperature related slight release pattern of the curcumin from the nanoparticles. In the next phase, the protective effect of curcumin nanoparticles and dexamethasone against cisplatin damage were tested on auditory cells and in a guinea pig model. The in vivo experiments included the auditory brainstem response, antioxidant enzyme assays and morphological assessment of the cochlea. The results of our experiments showed that a combination treatment of curcumin loaded nanoparticles and dexamethasone reduced cisplatin-induced degenerative changes both in vitro and in vivo.Le cisplatin est un agent chimiothérapeutique efficace qui cause des effets néfastes oxydatifs et inflammatoires à la cochlée, l'organe jouant un rôle primordial dans l'audition. Les changements dégénératifs de la cochlée suite au traitement avec le cisplatin entrainent une perte auditive permanente chez les patients, particulièrement chez les jeunes enfants. Le curcumin est un composant phytochimique qui peut exercer diverses propriétés biologiques, particulièrement comme agent antioxydant efficace. Dans cette étude, le curcumin a été encapsulé par des nanoparticules NIPAAM/VP/PEG-A afin d'augmenter la biodisponibilité du médicament. Notre hypothèse est qu'un traitement avec du curcumin encapsulé en nanoparticules en combinaison avec la dexaméthasone peut réduire le stress oxydatif et l'inflammation induite par le cisplatin à l'organe auditif. Dans une première étape, la caractérisation des nanoparticules de curcumine a montré une stabilité dans la matrice aqueuse, ainsi qu'une légère libération du curcumin des nanoparticules. Dans la phase suivante, l'effet protecteur des nanoparticules de curcumin combiné avec de la dexaméthasone contre les effets néfastes du cisplatin ont été testés sur des cellules auditives et un modèle de cochon d'inde. Les expériences in vivo comprenaient des réponses auditives cérébrales, des tests d'enzymes anti-oxydantes et des évaluations morphologiques de la cochlée. Les résultats in vitro et in vivo ont affirmé qu'un traitement de curcumin encapsulé en nanoparticules en combinaison avec la dexaméthasone réduit les changements dégénératifs induits par le cisplatin.
35
Odhah, M. S. "Cisplatin : Pharmacokinetic and biochemical studies in cancer patients." Thesis, Cardiff University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372341.
36
Edlin, Angela Rosalyn Margaret. "DNA damage recognition and p53 in cisplatin resistance." Thesis, University of Glasgow, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387598.
37
Orton, David Michael. "Insights into the mode of action of cisplatin." Thesis, University of York, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306541.
38
He, Qing 1973. "Understanding and improving the anticancer activity of cisplatin." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/44508.
Abstract:
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2001.Vita.
Includes bibliographical references.
The purpose of this thesis is to further our understanding of the mechanism of action of cis-diamminedichloroplatinum(II) (cisplatin), one of the most effective anticancer drugs. Since its serendipitous discovery in 1970, cisplatin has served to help cure testicular cancer and treat a variety of human malignancies. It is widely accepted that DNA is the cellular target for cisplatin. Prior to this work, several structures of duplex DNA modified by cisplatin revealed the distinctive distortions caused by cisplatin-DNA adducts. High mobility group (HMG) domain proteins are DNA binding proteins that bind to cisplatin-modified DNA in vitro with high specificity and affinity. HMG-domain proteins block nucleotide excision repair of cisplatin-DNA adducts in vitro, suggesting that such proteins may mediate cisplatin cytotoxicity in cells. The structure of HMG1 domain A bound to site-specifically cisplatin modified DNA reveals an unprecedented protein-DNA binding mode and a key phenylalanine side-chain intercalation. Factors contributing to the affinity of HMG-domain proteins for cisplatin-modified DNA are not well understood. In Chapter 2 is described a biochemical approach to evaluate the contribution of intercalating residues to the affinity of HMG-domain proteins for platinated DNA. Site-directed mutagenesis, bandshifts and footprinting methods show that the position of the side-chain intercalator determines the protein binding mode. This study provides a new paradigm to understand why and how HMG domains interact with platinated DNA. In addition to understanding the molecular basis of protein platinated-DNA interaction, the role of HMG-domain proteins in the cisplatin mechanism was investigated on the cellular level. Overexpression of HMG1 had been predicted to enhance the sensitivity of mammalian cells to cisplatin. Previous attempts from our laboratory and others failed to overexpress HMG1 stably in cells. When it was reported that HMG1 mRNA is upregulated in mammalian breast cancer MCF-7 cells after estrogen treatment, the effects of steroid hormone treatment on HMG1 protein expression and cisplatin sensitivity in mammalian cell lines from breast and ovarian tumors were studied. The ability to modulate cisplatin sensitivity in cells has useful clinical implications such as enhancing the efficacy of cisplatin chemotherapy. The results of this study led to a phase I clinical trial to investigate the efficacy of hormonecarboplatin combination therapy for treatment of ovarian cancer patients. It can concluded from Chapters 2 and 3 respectively, that the affinity of HMG domains for cisplatin-modified DNA can be improved by protein modifications and that the cytotoxicity of cisplatin can be enhanced by HMG1 overexpression. Because cisplatin lesions are not natural targets for HMG domain proteins, the protein-DNA binding affinity may not be optimal. It is of interest to design novel proteins to be used in gene therapy for further improvement of the therapeutic effects of cisplatin in patients. In order to achieve this goal, the phage display method was employed to search for novel HMG domain proteins with higher affinity for cisplatin-modified DNA than those naturally occurring. It was successfully demonstrated that HMG-domains can be expressed on the phage surface, and protocols were established to enable selection for cisplatin-damaged DNA targets based on DNA structure rather than sequence. Chapter 4 sets the foundation for future phage display protocols to design proteins of high affinity for cisplatin-modified DNA.
by Qing He.
Ph.D.
39
Fisher, Joshua. "In Vitro Binding Kinetics of ChemoFilter with Cisplatin." Thesis, University of California, San Francisco, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10165379.
Abstract:
Introduction: Endovascular chemotherapy treatment allows localized delivery adjacent to the target tumor; allowing an increased dosage and decreased leakage to other areas. It also allows for the opportunity to filter chemotherapy escaping the target tumor and entering the bloodstream. The ChemoFilter - a temporarily deployable, endovascular device will do just that; reducing systemic toxicity thus reducing adverse side effects from chemotherapy treatment. This will allow further increased dosage, increased tumor suppression, and increased tolerance to treatment. ChemoFilter has successfully filtered the chemotherapeutic Doxorubicin, but had yet to be tested in other chemotherapeutics. This study evaluates binding with new chemotherapeutics: Cisplatin, Carboplatin, and a cocktail comprised of Cisplatin and Doxorubicin.
Materials and Methods: ChemoFilter prototypes based on: 1.) Genomic DNA and 2.) Dowex (ion-exchange) resin, were evaluated for their ability to bind chemotherapy in vitro in phosphate-buffered saline (PBS). ChemoFilter was tested free in solution and encapsulated in nylon or polyester mesh packets of various dimensions. Concentrations were quantified using inductively coupled plasma mass spectrometry (IPC-MS), ultraviolet-visible spectrophotometry (UV-Vis), or fluorospectrometry. 11C, 13C, and/or 14C radiolabeling Carboplatin began for in vitro and in vivo ChemoFilter quantification. In vitro quantification can include scintillation and/or gamma counting. In vivo may include Positron Emission Tomography (PET) imaging, Hyperpolarized 13C Magnetic Resonance Imaging (MRI), and/or Magnetic Resonance Spectroscopy (MRS) for real-time visualization. Reactions were verified using High Performance Liquid Chromatography (HPLC) for chemical species identification.
Results and Discussion: Results indicate significant and nearly complete, ~99% (p<0.01) clearance of Cisplatin using the DNA ChemoFilter sequestered in Nylon mesh, quantified with gold standard ICP-MS (evidenced at 214 and 265 nm). The Ion-exchange ChemoFilter has significant clearance, within seconds, of both Doxorubicin and Cisplatin mixed in a cocktail solution. However, it appears some Cisplatin is binding to the Nylon Mesh itself. Size, shape, and material of the mesh have been optimized. A potential mechanism for 11C, 13C, or 14C radiolabeling of Carboplatin has been developed and early results have been successful. ChemoFilter works much more efficiently when sequestered in nylon packets of specific geometries. Significant improvements have been made to ChemoFilter, moving the device closer to clinical trials.
40
Carroll, Eilis. "Investigation into ubiquitin signalling in response to cisplatin." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/bb2af7ef-0130-4eb7-8758-937e1a8e1824.
Abstract:
Cisplatin is an anti-cancer drug that acts by introducing toxic DNA interstrand crosslinks into proliferating cells, causing both cytostatic and cytotoxic effects. Although various models of the interstrand crosslink (ICL) response have been proposed, none of them are complete and much still remains unknown about how this process is coordinated. By understanding more about how cisplatin and ICLs cause cell death, we may be able to optimise the use of current drugs, or identify novel targets for new chemotherapeutic drugs. It is known that ubiquitination is important for the regulation of the ICL response and it is thus probable that some ubiquitin-related proteins have previously unidentified roles in this process. This thesis describes the use of a robust high throughput siRNA screen to identify such novel ubiquitin-associated components of the response to cisplatin. Positive candidates were identified based on their ability to cause sensitivity to cisplatin and included both known and novel mediators of the ICL response. The siRNA screen formed an initial platform for further study of the roles of novel hits RNF113B, HOIP and ABIN1 in the DNA damage response. RNF113B was a previously uncharacterized E3 ligase. Studies described herein initially suggested that RNF113B might have a role in DNA repair after cisplatin treatment. However, final validation of a role for RNF113B in the ICL response was not forthcoming. HOIP is an E3 ubiquitin ligase that creates linear polyubiquitin chains as part of the linear ubiquitin assembly complex (LUBAC). LUBAC is required for innate and adaptive immunity, suppressing inflammation and the control of cell death through TNF and etoposide-induced signalling. HOIP was identified and validated as a top candidate of the siRNA screen. Within this thesis I show that cisplatin-induced caspase-3/7 activity is enhanced in HOIP-depleted cells, and corresponds with enhanced cisplatin-induced caspase-8 and -9 activities. Furthermore, HOIP depletion re-sensitises a cisplatin-resistant cancer line to cisplatin. Thus HOIP is an anti-apoptotic protein in the response to cisplatin and may be a potential target for anti-cancer therapeutics. ABIN1 is a polyubiquitin-binding protein involved in autoimmunity, inflammation and protecting cells from TNF-induced apoptosis. In this thesis I present data implying that ABIN1 also protects cells from cisplatin-induced cell death. ABIN1-deficient cells, including ubiquitin-binding deficient Abin1D485N/D485N MEFs, are hypersensitive to interstrand crosslinkers. DNA damage checkpoint and repair responses are mostly intact in ABIN1-deficient cells, while cisplatin-induced apoptosis is vastly enhanced. Furthermore, GFP-ABIN1 forms ubiquitin-binding dependant macro-molecular structures in the cytosol that resemble previously described ‘speckles’ seen in caspase-8 mediated apoptotic signalling. As HOIP creates linear chains that ABIN1 can bind to, and both proteins protect cells from cisplatin-induced apoptosis, I also discuss whether ABIN1 and HOIP may act together in the same pathway. In conclusion, the siRNA screen identified several potential targets as novel regulators of the response to cisplatin. Further investigations revealed that HOIP and ABIN1 protect cells from cisplatin-induced apoptosis, emphasising the importance of ubiquitin signalling in cell death and the DNA damage response.
41
Breaux, James Kelly. "Gene expression profiles indicative of response to cisplatin /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3090455.
42
Phelps, Jennifer Suzanne 1960. "CISPLATIN NEPHROTOXICITY: IN VITRO STUDIES (KIDNEY, TOXICOLOGY, PLATINUM)." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/291243.
43
SATHIYASEELAN, Theneshkumar. "Novel Oto-Protection Strategy in Cisplatin Induced Ototoxicity." Doctoral thesis, Università degli studi di Ferrara, 2009. http://hdl.handle.net/11392/2388666.
Abstract:
It has been almost forty years since cisplatin was introduced in clinical practice as a
potent and promising anti-neoplastic drug. Since then, the usage of cisplatin for treating a variety
of cancers in both children and young adults has increased. Ototoxicity is one of the dose
limiting side effects of cisplatin. Currently, there is not a single good otoprotecting drug against
cisplatin ototoxicity in clinical practice.
We planed to study the effect of noise stress against cisplatin ototoxicity alone and in
combination with two other thiol based otoprotectors, namely L-NAC and D-MET, at very low
dosages which had shown otoprotection against cisplatin ototoxicity. Although these two
otoprotectors have shown promising results in animal studies at high dosages, there is concern
that high dose of L-NAC and D-MET could have negative effects on chemotherapy, leading to
reduced chemotherapeutic efficacy. In an attempt to avoid this negative chemotherapeutic effect,
studies have been conducted administrating the otoprotecting drug at varying times and space.
The underlined hypothesis of this thesis is that a tolerable stress before an intolerable
cisplatin insult could better prepare the hair cells for the intolerable cisplatin insult. Above all, an
acute noise stress alone could potentially activate antioxidant enzymes, heat shock proteins,
glucocorticoids, and stress activated protein kinases that could protect the hair cells from
cisplatin toxicity.
We used noise stress to enhance the otoprotective effects of L-NAC and D-MET.
Moreover, we were interested in studying the effect of noise stress alone.
Results of our studies have demonstrated that the noise stress technique maximizes the
otoprotecting efficacy of 275 mg/kg L-NAC and 300 mg/kg D-MET, where 300 mg/kg D-MET
+ noise stress being the best among all treated groups. More interestingly, we found that noise
stress alone showed better results against cisplatin ototoxicity when compared with the cisplatin
only group. Both Hematoxylin and Eosin staining and TRITC-conjugated phalloidin staining
were essentially consistent with the ABR findings.
Even minor otoprotection by an acute noise stress could change the current course of
drug-only otoprotection approach against cisplatin ototoxicity. In clinic, this would let us use
certain frequencies of sound by a headphone before or after the cisplatin treatment to protect at
least the speech perception frequencies of patients.
44
Scaramel, Fernanda dos Santos. "Avaliação da inativação de cisplatina, doxorrubicina e paclitaxel utilizando soluções de asepto 75® 0,5%, hipoclorito de sódio 10% e tiossulfato de sódio 10%." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/9/9139/tde-26012017-112701/.
Abstract:
Os agentes antineoplásicos são considerados drogas de risco, ou seja, aquelas que podem ocasionar efeitos como genotoxicidade, carcinogenicidade , teratogenicidade ou alteração na fertilidade e a exposição dos profissionais de saúde constitui-se em grande preocupação do ponto de vista de saúde ocupacional. Precedendo o seu emprego na terapia oncológica, estes medicamentos devem ser submetidos a análises físicas, químicas e biológicas para avaliação da qualidade, sendo que estes testes geram considerável volume de resíduos que também requerem tratamento. O objetivo deste trabalho foi avaliar a eficácia de diferentes métodos de inativação para as moléculas de cisplatina, doxorrubicina e paclitaxel em solução injetável, utilizando cromatografia líquida de alta eficiência (avaliação química) e teste de citotoxicidade in vitro (avaliação biológica). Foram avaliados os inativantes Asepto 75® (solução a 0,5%), hipoclorito de sódio (solução a 10%) e tiossulfato de sódio (solução a 10%). Os ativos ficaram expostos aos inativantes por períodos que variaram de 0 a 6 horas. Os resultados demonstraram que o asepto 75 é eficiente para a inativação química e biológica dos três ativos, sendo o tempo de exposição fator determinante para a degradação química da cisplatina. Os graus de citotoxicidade variaram de nenhum a leve (IZ= 0 a 1). O hipoclorito de sódio possui um grau de citotoxicidade por si só, porém foi eficaz na inativação química dos três ativos. Já o inativante tiossulfato de sódio se mostrou eficaz na in ativação química da cisplatina, não tendo efeito sobre a doxorrubicina ou sobre o paclitaxel. Os resultados da avaliação in vitro mostraram-se compatíveis com os da avaliação química. Conclui-se que a inativação dos princípios ativos previamente ao descarte é eficaz para reduzir os riscos ocupacionais e ambientais das drogas citotóxicas.The anti-neoplastic agents are considered risk drugs, that is, the ones that can cause effects, such as genotoxicity, carcinogenicity, teratogenicity or change in fertility. Because of these factors, the exposure of the health care professionals are a great concern of occupational health. Before the use of the oncological therapy, these drugs should be undergone to the physical, chemical and biological tests for the quality evaluation, considering that these test also produce a considerable amount of waste which also demand treatment. The aim of this work is to evaluate the efficacy oh the different methods of inactivation for the cisplatine molecules, doxorubicine and paclitaxel in injection solutions. Using high performance liquid chromatography (chemical evalution) and in vitro citotoxity test (biological evaluation). It has been evaluated Asepto 75 degradant (aqueous solution at 0,5%), sodium hypochlorite (aqueous solution at 10%) and sodium thyosulfate (aqueous solution at 10%). The drugs were exposed to the degradants in periods that ranged from 0 to 6 hours. The results have been demonstrated that asepto 75 is efficient for the chemical and biological inativation of the drugs, and the time of exposition is determinant for the chemical degradation of cisplatin. The citotoxicity grades have ranged from \"none\" to \"slight\". The sodium hypochlorite has a toxicity grade for itself, although it was effective in the chemical degradation of the three drugs. Yet the sodium thiosulfate degradant has demonstrated to be effective in the chemical inativation of cisplatin, not having effects over doxorubicin or paclitaxel. The results of in vitro evaluation have been compatible with the chemical evaluation. It concludes that the inactivation of the drugs before the waste is effective to reduce the occupational and environmental risks of citotoxic drugs.
45
Mendonça, Leonardo Meneghin. "Avaliação genotóxia e antigenotóxica da curcumina contra a toxicidade induzida pela cisplatina em culturas de células PC12." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/60/60134/tde-14092008-220103/.
Abstract:
Pode-se dizer que o câncer, ao lado da AIDS, é a doença que atinge, a níveis mundiais, maior clamor da sociedade por desenvolvimento de cura e melhor qualidade de vida ao paciente. Várias terapias são utilizadas para o tratamento do câncer, podendo-se destacar a importância da quimioterapia em inúmeros protocolos de tratamento. Um dos fármacos mais antigos e mais utilizados na quimioterapia é a cisplatina, que ao longo dos seus mais de 30 anos na prática clínica demonstrou sua eficácia e foi incorporada no protocolo de tratamento de uma variedade de tumores. Entretanto, ao lado se sua comprovada eficácia, é inerente o desenvolvimento de vários efeitos colaterais resultante de sua toxicidade à células sadias. Neste trabalho, destaque é dado a neurotoxicidade, que surge em um grande número de pacientes que recebem tratamento com a cisplatina. Inúmeros esforços têm sido realizados na tentativa de prevenir ou controlar os efeitos tóxicos induzidos pela cisplatina, com atenção especial à suplementação do tratamento quimioterápico com compostos antioxidantes. Nesse sentido, este estudo visa avaliar a associação da curcumina, um composto polifenólico com notável atividade antioxidante e neuroprotetora, ao tratamento com cisplatina, em um modelo in vitro com culturas de células PC12. A curcumina é reconhecidamente um composto polifenólico com um amplo espectro de atividades biológicas, com suas propriedades neuroprotetoras demonstradas em vários modelos estudados estando principalmente relacionadas com seu potencial antioxidante. Os múltiplos mecanismos de ação dos compostos fenólicos e suas propriedades neuroprotetoras atribuídas a capacidade de inibição das espécies reativas de oxigênio indicam um potencial de inibição da neurotoxicidade que surgem durante o tratamento quimioterápico com a cisplatina, visto a reconhecida capacidade de geração de espécies reativas de oxigênio da cisplatina. Como a geração de espécies reativas de oxigênio intracelular pode resultar em danos ao DNA pela ação direta das espécies reativas ou indiretamente via produtos de degradação da peroxidação lipídica, nosso estudo avaliou o potencial protetor da curcumina contra a genotoxicidade induzida pela cisplatina em culturas de células PC12, analisando a indução de micronúcleos e a análise de quebras de cadeia simples, cadeia dupla do DNA e sítios álcali-labeis pelo ensaio do cometa. Antes da avaliação antigenotóxica da curcumina, foi realizada uma avaliação citotóxica e genotóxica, em que pode-se observar que em concentrações elevadas a curcumina é citotóxica e genotóxica às células PC12. O efeito protetor da curcumina foi avaliado em pré-tratamento das culturas de células PC12 com concentrações não tóxicas. Nas três concentrações de curcumina estudadas não houve indícios de interferência com a citotoxicidade ou o efeito citostático da cisplatina. Embora o efeito protetor da curcumina contra os danos induzidos ao DNA de células PC12 não tenha sido evidente nos resultados obtidos pelo ensaio do cometa, a curcumina foi eficaz na redução de micronúcleos induzidos pela cisplatina, de maneira semelhante nas três concentrações avaliadas. Os resultados positivos obtidos nesse estudo juntamente com os dados pré-existentes a respeito de efeitos protetores da curcumina incentivam novas pesquisas em relação aos possíveis benefícios da utilização da curcumina em terapia combinada aos quimioterápicos.Several therapies are used for treating cancer and the importance of chemotherapy can be emphasized in many protocols of treatment. One of the oldest and most used drugs in chemotherapy is the cisplatin which, with its more than thirty years of clinical practice, has demonstrated its effectiveness being incorporated into the protocol of a variety of tumor treatments. On the other hand, it is intrinsic the development of various side effects resulting from its toxicity to healthy cells. This research gives emphasis to the neurotoxicity which appears in a large number of patients receiving the cisplatin treatment. Numerous efforts are being made in attempt to prevent or even control the toxic effects induced by cisplatin with special attention being given to the supplementation of chemotherapy treatment with antioxidant compounds. In that sense, this study aims to assess the association of curcumin, a polifenolic compound with remarkable antioxidant and neuroprotective activity, to the cisplatin treatment in an in vitro neuronal model with PC12 cell cultures. The curcumin is admittedly a polifenolic compound with a broad spectrum of biological activities and their neuroprotective properties, demonstrated in several models, are strongly related to its antioxidant potential. The multiple mechanisms of action of the phenolic compounds and their neuroprotective properties credited to the ability of inhibition of the reactive oxygen species indicate a potential inhibition of neurotoxicity that takes place during the chemotherapy treatment with cisplatin, given its well known ability to generate reactive oxygen species. Since the generation of reactive oxygen species intracellular can result in DNA damage by direct action of reactive species or indirect, through degradation products of the lipid peroxidation, our studies evaluated the potential protector of curcumin against the genotoxicity induced by cisplatin in PC12 cell cultures by examining the induction of micronuclei and analyzing DNA single strand breaks, double strand breaks, and alkali-labeis sites through the comet test. Before the antigenotoxic evaluation of the curcumin, a cytotoxic and genotoxic test was conducted where it was observed that when in high concentrations the curcumin is cytotoxic and genotoxic to the PC12 cells. The protective effect of curcumin was evaluated at the pre-treatment of PC12 cell cultures with non-toxic levels of concentration. In the three studied curcumin concentrations there was no evidence of interference with the cytotoxicity or cytostatic effect of the cisplatin. Although the protective effect of the curcumin put against the damage caused to the DNA of cells PC12 was not evident in the results obtained by the comet test, the curcumin was equally effective in the reduction of micronuclei induced by the cisplatin in all three concentrations evaluated. The positive results obtained in this study combined with the pre-existing data about the protective effects of the curcumin encourage some more new research on possible benefits of using curcumin in combination to chemotherapy.
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Machado, Carla da Silva. "Possíveis efeitos citoprotetores do antioxidante da dieta coenzima Q10 em modelo de células neuronais." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/60/60134/tde-24102011-143836/.
Abstract:
A coenzima Q10 é uma provitamina lipossolúvel sintetizada endogenamente e naturalmente encontrada em alimentos como a carne vermelha, peixes, cereais, brócolis e espinafre. É comercializada como suplemento alimentar e utilizada em formulações cosméticas. Localiza-se na membrana de organelas celulares como retículo endoplasmático, vesículas e membrana interna da mitocôndria, onde atua como um cofator essencial na cadeia respiratória. Apresenta propriedades antioxidantes e potencial no tratamento de doenças neurodegenerativas e neuromusculares. O objetivo deste trabalho foi investigar os possíveis efeitos protetores de uma formulação hidrossolúvel de coenzima Q10 em células PC12 expostas à cisplatina, um fármaco antineoplásico que tem a neurotoxicidade como um dos fatores limitantes à sua utilização. A linhagem celular PC12 (feocromocitoma de ratos) utilizada nesta investigação é um reconhecido modelo in vitro para estudos neuronais. Os métodos empregados foram os ensaios do MTT, cometa, citoma micronúcleo com bloqueio da citocinese, crescimento de neuritos e análise da expressão do gene Tp53. Os resultados obtidos na avaliação da citotoxicidade da coenzima Q10 (0,1 - 20 µg/mL) mostraram que este antioxidante foi citotóxico às células PC12 na concentração de 20,0 µg/mL e não apresentou citotoxicidade em baixas concentrações. Para os ensaios do citoma e cometa, foram selecionadas três concentrações não citotóxicas de coenzima Q10 (0,1; 0,5 e 1,0 µg/mL) que não apresentaram mutagenicidade e genotoxicidade às células PC12. O efeito protetor da coenzima Q10 sobre a cisplatina no ensaio do citoma foi caracterizado pela diminuição da freqüência de micronúcleos e brotos nucleares, entretanto a proteção da coenzima Q10 não foi evidenciada no ensaio cometa. Alterações significativas na expressão do gene Tp53 não foram observadas no tratamento coenzima Q10 (1,0 µg/mL) associado à cisplatina (0,1 µg/mL). A coenzima Q10 (0,1 e 1,0 µg/mL) não foi neurotóxica em células PC12 indiferenciadas e diferenciadas após exposição ao fator de crescimento do nervo, e seu melhor efeito neuroprotetor foi observado na menor concentração avaliada. A coenzima Q10 reduziu a citotoxicidade da cisplatina (10,0 µg/mL) em células PC12 indiferenciadas e estimulou o crescimento de neuritos em células PC12 diferenciadas. A determinação dos efeitos citoprotetores da coenzima Q10 em um modelo neuronal é importante para elucidar possíveis estratégias de neuroproteção que poderiam ser aplicadas aos pacientes submetidos à quimioterapia.Coenzyme Q10 is a liposoluble provitamin endogenously synthesized and naturally found in various foods items, such as meat, fish, cereals, broccoli and spinach. It is a dietary supplement in some countries and used in cosmetic formulations. Coenzyme Q10 is located in the membrane of cellular organelles such as endoplasmic reticulum, vesicles and inner mitochondrial membrane, where acts as an essential cofactor in the respiratory chain. It has antioxidant properties and potential in the treatment of neurodegenerative and neuromuscular diseases. The objective of this study was to investigate the possible protective effects of a water-soluble formulation of coenzyme Q10 in PC12 cells exposed to cisplatin, an anticancer drug that has neurotoxicity as a dose-limiting factor. The PC12 cell line (rat pheocromocytoma) used in this investigation is a recognized in vitro model for neuronal studies. The methods used were the MTT, comet, cytokinesis-block micronucleus cytome, neurite outgrowth assays and expression of Tp53 gene. The results obtained in the cytotoxicity of coenzyme Q10 (0.1-20 µg/mL) showed that this antioxidant was cytotoxic to PC12 cell at a concentration of 20.0 µg/mL and it was not cytotoxic at low concentrations. For the cytome and comet assays, were selected three non-cytotoxic concentrations of coenzyme Q10 (0.1, 0.5 and 1.0 µg/mL) without mutagenicity and genotoxicity PC12 cells. The protective effect of coenzyme Q10 in cytome assay was characterized by decreased frequency of micronuclei and nuclear buds induced by cisplatin, however the protection of coenzyme Q10 was not evidenced by the comet assay. No significant change in the Tp53 gene expression were observed in the coenzyme Q10 (1.0 µg/mL) plus cisplatin (0.1 µg/mL) treatment. Coenzyme Q10 (0.1 and 1.0 µg/mL) was not neurotoxic in undifferentiated and nerve growth factor differentiated PC12 cells and the lowest concentration evaluated showed the best neuroprotective effect. The coenzyme Q10 treatment reduced the citotoxicity of cisplatin (10.0 µg/mL) in undifferentiated PC12 cells and stimulated the neurite outgrowth in differentiated PC12 cells. Determination of the cytoprotective effects of the coenzyme Q10 in a neuronal model is important to elucidate possible strategies for neuroprotection that could be applied to patients undergoing chemotherapy.
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Robey, Stephanie. "Reactions of Platinum(II) Compounds with Selenium Containing Amino Acids." TopSCHOLAR®, 2013. http://digitalcommons.wku.edu/theses/1252.
Abstract:
Platinum(II) anticancer medications essentially react with DNA forming kinks inthe double helix of DNA and causing apoptosis. It has also been noted that theseanticancer medications react with methionine and cysteine in the body. With the new discoveries of selenium containing amino acids including selenomethionine and selenocysteine, new research is ongoing to see what types of products can be formed from these amino acids. Our research reacts [Pt(Met-S,N)Cl2] 2+ with selenomethionine to determine what types of products are produced. Monochelates including [Pt(SeMet-Se,N)Cl2] 2+ have formed two isomers, as well as other products that insinuate both selenomethionine and methionine binding with the platinum to form various [Pt(SeMet- Se,N)(Met-S,N)]2+ products. When initially reacting 6 mM [Pt(Met-S,N)Cl2] 2+ with 3 mM SeMet, the monochelates of both are produced without forming any free methionine which would suggest that there is free platinum in our solution creating the SeMet monochelate. When adding additional SeMet to the solution the same products are formed that are created when reacting 6 mM [Pt(Met-S,N)Cl2] 2+ and 6 mM SeMet. The 1H NMR spectrum for these products imply a product of [Pt(SeMet-Se,N)(Met-S,N)] 2+. Also, reactions with [Pt(en)(ox)] 2+ and SeMet were conducted and produced various products at two different pH’s. A [Pt(SeMet-Se,N2] 2+ product was formed at lower pH and produced free ethylenediamine, however at a higher pH only [Pt(en)(SeMet-Se,N)]2+ was produced.
48
Chau, Quincy Ka-Hing. "Cisplatin efflux, binding and intracellular pH in the HTB56 human lung adenocarcinoma cell line and the E-8/0.7 cisplatin-resistant variant." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0005/MQ46559.pdf.
49
Menardo, Julien. "Effets des dommages de l'ADN et du stress oxydant sur la dégénérescence des structures neuroépithéliales de la cochlée lors de l'intoxication au cisplatine et au cours du vieillissement." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T012.
Abstract:
Dans nos sociétés modernes, la presbyacousie, perte de l'audition liée au vieillissement, prend une place de plus en plus importante. Outre le vieillissement de la population, la prévalence de la presbyacousie est accentuée par l'exposition à des bruits toujours plus forts (concerts, baladeurs, environnement de travail, ...) et la prise de médicaments ototoxiques (cisplatine, aminoglycosides, ...). À ce jour, le lien entre l'endommagement de l'ADN, le stress oxydant et l'inflammation avec l'apparition précoce de certaines maladies liées au vieillissement (Alzheimer, démence, Parkinson, …) a été démontré. Cependant, il n'existe aucune donnée concernant le rôle des dommages de l'ADN dans la dégénérescence des cellules cochléaires et trop peu d'études témoignent de l'existence d'un stress oxydant dans la presbyacousie.Le premier objet de ce travail a donc été d'élucider le rôle des dommages de l'ADN dans la dégénérescence des cellules cochléaires. Pour ce faire, nous avons utilisé des approches de biologie moléculaire et cellulaire pour identifier des voies de signalisation associées aux lésions de l'ADN dans des explants cochléaires issus de souris âgées de 3 jours traités au cisplatine (CDDP). Cet antinéoplasique tire sa cytotoxicité de sa capacité à causer directement des dommages dans l'ADN et est connu pour ses effets nocifs sur l'audition en induisant la dégénérescence des cellules cochléaires. Enfin, nous avons étudié l'implication de p53, un des effecteurs clés de signalisation des dommages de l'ADN, in vivo en traitant avec le CDDP des souris dont le gène codant pour ce facteur de transcription a été invalidé. Nos résultats montrent que le CDDP induit des cassures double brin dans l'ADN des cellules ciliées qui sont à l'origine de l'activation de la voie ATM/DNA¬PK-Chk2-p53, de la formation de foyers βH2AX et 53BP1 et, in fine, de la mort de ces cellules par apoptose. Les cellules ciliées internes, plus résistantes au CDDP que les cellules ciliées externes, présentent une signalisation moins intense et un nombre inférieur de cassures double brin, un phénomène qui pourrait expliquer leur plus faible sensibilité. Nous avons également montré que l'absence de p53 in vivo prévient les pertes d'audition et la dégénérescence des cellules ciliées externes après injection intrapéritonéale de CDDP. Le second objectif a porté sur l'étude des effets délétères du vieillissement sur l'audition et les mécanismes moléculaires associés à cette pathologie. Pour ce faire, nous avons choisi les souris SAMP8 (senescence accelerated mice prone 8), un modèle bien établi de sénescence précoce et des maladies liées au vieillissement. Nous avons combiné des approches fonctionnelles, morphologiques, moléculaires et cellulaires pour phénotyper ces souris et identifier l'origine de l'atteinte de leur audition au cours du vieillissement. L'étude des souris SAMP8 nous a permis de montrer qu'elles sont un excellent modèle de presbyacousie mixte (atteinte de la strie vasculaire, de l'organe de Corti et du ganglion spiral), résumant la pathologie humaine. La dégénérescence des structures cochléaires que nous avons observée chez ces souris provient d'une profonde dysfonction mitochondriale, de l'augmentation du stress oxydant et des processus inflammatoires, d'un stress autophagique et de l'endommagement de l'ADN. Les mécanismes moléculaires aboutissant à la perte des cellules cochléaires constituent autant de cibles thérapeutiques à explorer dans l'avenir afin de tenter de prévenir les troubles de l'audition imputables à l'exposition au bruit ou aux médicaments ototoxiques et au vieillissementOur modern society is confronted with a dramatic increase in the number of patients suffering from presbycusis or age related hearing loss. Besides aging, presbycusis prevalence increases with exposition to loud noise (concerts, Walkman, work environment …) and ototoxic drugs (cisplatin, aminoglycosides …). It was reported that the early onset of some aging related diseases (Alzheimer, dementia, Parkinson …) are linked mechanistically to DNA damage, oxidative stress and inflammation. However, the role of DNA damages in cochlear cells degeneration is totally unknown and only few studies have investigated the implication of oxidative stress in presbycusis.The first goal of this study consisted in clarifying the role of DNA damage in cochlear cell degeneration. For this purpose, we used molecular and cellular biology approaches to identify the activation of DNA damage response pathways in cisplatin (CDDP) treated 3 days postnatal mouse cochlear explants in culture. Indeed, the cytotoxicity of CDDP arises from its capacity to directly damage DNA. It is also well known that one of the major dose limiting side effects of CDDP is its ototoxicity. Finally, we investigated the role of p53, a key effector of the DNA damage response pathway, in vivo by treating p53 knockout mice with CDDP. Our results show that CDDP induces double strand breaks leading to the activation of ATM-/DNA PK¬ Chk2 p53 pathway, βH2AX and 53BP1 foci formation and, in fine, apoptotic cell death. Inner hair cells, which are more resistant to CDDP treatment than outer hair cells, show a less intense signaling and fewer double strand breaks. This phenomenon could explain their weaker sensitivity to CDDP treatment. In vivo, p53 deletion prevents hearing loss and outer hair cells degeneration induced bay intraperitoneal injection of CDDP.The second goal consisted in studying the deleterious effects of aging on hearing and the molecular mechanisms involved in this pathology. Here, we studied the mechanism of presbycusis using the senescence-accelerated mouse prone 8 (SAMP8) which is a useful model to probe the effects of aging on biological processes. Based on complementary approaches combining functional, morphological, biochemistry, cellular and molecular biology, we found that the SAMP8 strain displays premature hearing loss and cochlear degeneration recapitulating the processes observed in human presbycusis (i.e. strial, sensory and neural degeneration). The molecular mechanisms associated with premature presbycusis in SAMP8 mice involve oxidative stress, mitochondrial dysfunction, chronic inflammation, autophagic stress and DNA damages. Molecular mechanisms leading to cochlear cells loss represent therapeutic targets of interest to explore in the future in order to prevent hearing impairments due to loud sound or ototoxic drugs exposure and due to aging
50
Conway, Emma. "Cisplatin partially impedes lung adenocarcinoma-mediated M2 macrophage polarization." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/56408.
Abstract:
Lung cancer is the leading cause of cancer mortality and at 18%, has one of the lowest five-year survival rates of all malignancies. The majority of patients (>80%) are diagnosed with locally advanced or metastatic disease for which the standard of care is platinum-based doublet chemotherapy. However, chemotherapy has modest effects on overall survival, highlighting the need for novel and more effective treatments.
Within the past decade, the role of the immune system in tumorigenesis has become increasingly appreciated. Targeting the immune cells within the tumor microenvironment is a growing field of study that holds exciting therapeutic potential. Macrophages are a prominent immune cell type in the lung and lung tumors. It is widely accepted that a spectrum of macrophage activation states exists, with the exact phenotype dependent upon the precise composition of signals within the microenvironment. At opposite ends of this spectrum there exist M1 macrophages which are pro-inflammatory and have antitumor functions, and M2 macrophages which are anti-inflammatory and act in wound healing and thus promote tumorigenesis. I hypothesized that macrophage differentiation is skewed by lung adenocarcinoma cells to an M2 phenotype and that cisplatin, a commonly prescribed chemotherapeutic, affects macrophage polarity. I co-cultured human monocytes with human lung adenocarcinoma cells in the absence and presence of physiologically relevant concentrations of cisplatin. Co-cultured macrophages displayed increased differentiation and an M2 polarity, in part potentially through IL-6 secretion by tumor cells. Cisplatin impeded macrophage differentiation, with treated macrophages displaying decreased size, granularity, and surface marker expression; however, CD206 expression, an M2 marker, remained elevated, suggesting a role for CD206 in response to treatment. Additionally, I optimized single cell analysis of clinical specimens in preparation for future projects, specifically ex vivo analysis of the effect of standard first line chemotherapy on macrophage polarity and other immune cells in advanced non-small cell lung cancer. Collectively, this work has demonstrated that macrophage polarity is affected by lung adenocarcinoma cells and by cisplatin. Moreover, the optimization of single cell analysis has prepared for the study of the effect of chemotherapy on macrophage polarity over the course of treatment using more physiologically representative specimens.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate