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1.
Tumour Biol ; 39(10): 1010428317695933, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29019283

RESUMO

Peritoneal carcinomatosis is considered as a potentially lethal clinical condition, and the therapeutic options are limited. The antitumor effectiveness of the [Ru(l-Met)(bipy)(dppb)]PF6(1) and the [Ru(l-Trp)(bipy)(dppb)]PF6(2) complexes were evaluated in the peritoneal carcinomatosis model, Ehrlich ascites carcinoma-bearing Swiss mice. This is the first study that evaluated the effect of Ru(II)/amino acid complexes for antitumor activity in vivo. Complexes 1 and 2 (2 and 6 mg kg-1) showed tumor growth inhibition ranging from moderate to high. The mean survival time of animal groups treated with complexes 1 and 2 was higher than in the negative and vehicle control groups. The induction of Ehrlich ascites carcinoma in mice led to alterations in hematological and biochemical parameters, and not the treatment with complexes 1 and 2. The treatment of Ehrlich ascites carcinoma-bearing mice with complexes 1 and 2 increased the number of Annexin V positive cells and cleaved caspase-3 levels and induced changes in the cell morphology and in the cell cycle phases by induction of sub-G1 and G0/G1 cell cycle arrest. In addition, these complexes reduce angiogenesis induced by Ehrlich ascites carcinoma cells in chick embryo chorioallantoic membrane model. The treatment with the LAT1 inhibitor decreased the sensitivity of the Ehrlich ascites carcinoma cells to complexes 1 and 2 in vitro-which suggests that the LAT1 could be related to the mechanism of action of amino acid/ruthenium(II) complexes, consequently decreasing the glucose uptake. Therefore, these complexes could be used to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. Besides, these complexes induce apoptosis by combination of different mechanism of action.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Ehrlich/patologia , Neoplasias Peritoneais/patologia , Compostos de Rutênio/farmacologia , Aminoácidos/farmacologia , Animais , Western Blotting , Camundongos
2.
Biometals ; 27(3): 459-69, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24781824

RESUMO

Lung cancer is one of the leading causes of death in the world, and non-small cell lung carcinoma accounts for approximately 75-85 % of all lung cancers. In the present work, we studied the antitumor activity of the compound cis-(dichloro)tetramineruthenium(III) chloride {cis-[RuCl2(NH3)4]Cl} against human lung carcinoma tumor cell line A549. The present study aimed to investigate the relationship between the expression of MDR1 and CYP450 genes in human lung carcinoma cell lines A549 treated with cisCarboPt, cisCRu(III) and cisDRu(III). The ruthenium-based coordinated complexes presented low cytotoxic and antiproliferative activities, with high IC50 values, 196 (±15.49), 472 (±20.29) and 175 (±1.41) for cisCarboPt, cisCRu(III) and cisDRu(III), respectively. The tested compounds induced apoptosis in A549 tumor cells as evidenced by caspase 3 activation, but only at high concentrations. Results also revealed that the amplification of P-gp gene is greater in A549 cells exposed to cisCarboPt and cisCRu(III) than cisDRu(III). Taken together all these results strongly demonstrate that MDR-1 over-expression in A549 cells could be associated to a MDR phenotype of these cells and moreover, it is also contributing to the platinum, and structurally-related compound, resistance in these cells. The identification and characterization of novel mechanisms of drug resistance will enable the development of a new generation of anti-cancer drugs that increase cancer sensitivity and/or represent more effective chemotherapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carboplatina/farmacologia , Compostos Organometálicos/farmacologia , Compostos de Rutênio/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , L-Lactato Desidrogenase/metabolismo , Neoplasias Pulmonares
3.
Arq Bras Oftalmol ; 78(2): 89-93, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25945529

RESUMO

PURPOSE: To assess the cytotoxicity and genotoxicity of intravitreal adalimumab treatment in an animal experimental model using cytological and molecular techniques. METHODS: Eighteen rabbits were randomly assigned to three groups: control, adalimumab treatment, and placebo. Cytotoxicity on retinal cells was evaluated using flow cytometry assays to determine the level of apoptosis and necrosis. Genotoxicity was evaluated by comet assays to assess DNA damage, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate expression of apoptosis-inducing caspases (8 and 3). RESULTS: No cytotoxicity or genotoxicity was observed in any of the two treatment groups (adalimumab and placebo) following intravitreal administration compared with the control group. Flow cytometry analysis revealed that more than 90% of the cells were viable, and only a low proportion of retinal cells presented apoptotic (~10%) or necrotic (<1%) activity across all groups. Molecular damage was also low with a maximum of 6.4% DNA degradation observed in the comet assays. In addition, no increase in gene expression of apoptosis-inducing caspases was observed on retinal cells by qPCR in both the adalimumab and placebo groups compared with the control group. CONCLUSION: The use of adalimumab resulted in no detectable cytotoxicity or genotoxicity on retinal cells for up to 60 days upon administration. These results therefore indicate that adalimumab may be a safe option for intravitreal application to treat ocular inflammatory diseases in which TNF-α is involved.


Assuntos
Anti-Inflamatórios/toxicidade , Anticorpos Monoclonais Humanizados/toxicidade , Injeções Intravítreas/métodos , Retina/efeitos dos fármacos , Adalimumab , Animais , Apoptose/efeitos dos fármacos , Caspase 3/análise , Caspase 3/efeitos dos fármacos , Caspase 8/análise , Caspase 8/efeitos dos fármacos , Sobrevivência Celular , Ensaio Cometa , Dano ao DNA , Citometria de Fluxo , Masculino , Modelos Animais , Necrose , Coelhos , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Fator de Necrose Tumoral alfa/efeitos dos fármacos
4.
Springerplus ; 3: 301, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25019046

RESUMO

Chemotherapy is a common treatment for leukemia. Ruthenium complexes have shown potential utility in chemotherapy and photodynamic therapy. The identification of new chemotherapeutics agents is critical for further progress in the treatment of leukemia. Ruthenium complexes generally have lower toxicities compared to cisplatin attributed to their specific accumulation in cancer tissues. Based on these evidences, in the present work we studied the cytotoxic activity of the ruthenium(III) compound cis-tetraammine(oxalato)ruthenium(III) dithionate - {cis-[Ru(C2O4)(NH3)4]2(S2O6)} against human chronic myelogenous leukemia cells (K-562) tumor cell line. The tested compound induces cell death in a dose and time dependent manner on K-562 cells. It is found that the effect was improved linearly while prolonging the incubation time. Compared to the cell cycle profiles of untreated cells, flow cytometric analysis indicated the sub-G1 arresting effect of ruthenium compound on K-562 cells. In our study, {cis-[Ru(C2O4)(NH3)4]2(S2O6)} shows a significant increase in tailed cells in any of the concentrations tested compared with negative control. Consequently, the concentration of {cis-[Ru(C2O4)(NH3)4]2(S2O6)} might be associated cytotoxicity with direct effect on K-562 cells DNA. Thus, it can be deducted that ruthenium-based compounds present selectivity to enter both tumor and normal cells. Additional studies are needed to determine the molecular mechanisms of the active components and to evaluate the potential in vivo anticancer activity of the cis-tetraammine(oxalato)ruthenium(III) dithionate.

5.
Biol Trace Elem Res ; 147(1-3): 8-15, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22144016

RESUMO

Lung cancer is one of the leading causes of death in the world, and non-small cell lung carcinoma (NSCLC) accounts for approximately 75-85% of all lung cancers. In the present work, we studied the cytotoxic activity, cell cycle arrest and induction apoptosis of the compound cis-(dichloro)tetramineruthenium(III) chloride {cis-[RuCl(2)(NH(3))(4)]Cl} in human lung carcinoma tumor cell line A549. The results of MTT and trypan blue assays showed that cis-[RuCl(2)(NH(3))(4)]Cl causes reduction in the viability of A549 cells when treating with 95 and 383 µM of the compound for 48 and 72 h. Lower concentrations of the compound (19, 3.8 and 0.38 µM), however, only slightly affected cell viability. The IC(50) value for the compound was about 383 µM. Survival analysis of the A549 cells after treatment with ruthenium(III) compound using long term clonogenic assay showed that it reduced colony formation ability at concentrations of 0.38 and 3.8 µM, and at concentrations of 95 and 383 µM no colonies were observed. Cell cycle analysis showed that compound ruthenium led to an accumulation of A549 cells in S phase and increased in the sub-G1 peak. In addition, cis-(dichloro)tetramineruthenium(III) chloride treatment induced apoptosis, as observed by the increased numbers of annexin V-positive cells and increased messenger RNA expression of caspase-3.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Compostos de Rutênio/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Citometria de Fluxo , Fase G1/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Compostos de Rutênio/química , Fase S/efeitos dos fármacos
6.
Biol Trace Elem Res ; 133(3): 270-83, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19590831

RESUMO

Ruthenium compounds in general are well suited for medicinal applications. They have been investigated as immunosuppressants, nitric oxide scavengers, antimicrobial agents, and antimalarials. The aim of this study is to evaluate the immunomodulatory activity of cis-(dichloro)tetraammineruthenium(III) chloride (cis-[RuCl(2)(NH(3))(4)]Cl) on human peripheral blood mononuclear cells (PBMC). The cytotoxic studies performed here revealed that the ruthenium(III) complex presents a cytotoxic activity towards normal human PBMC, only at very high concentration. Results also showed that cis-[RuCl(2)(NH(3))(4)]Cl presents a dual role on PBMC stimulating proliferation and interleukin-2 (IL-2) production at low concentration and inducing cytotoxicity, inability to proliferate, and inhibiting IL-2 production at high concentration. The noncytotoxic activity of cis-[RuCl(2)(NH(3))(4)]Cl at low concentration towards PBMC, which correlates with the small number of annexin V positive cells and also the absence of DNA fragmentation, suggest that this compound does not induce apoptosis on PBMC. For the first time, we show that, at low concentration (10-100 microg L(-1)), the cis-[RuCl(2)(NH(3))(4)]Cl compound induces peripheral blood lymphocytes proliferation and also stimulates them to IL-2 production. These results open a new potential applicability of ruthenium(III) complexes as a possible immune regulatory compound acting as immune suppressor at high concentration and as immune stimulator at low concentration.


Assuntos
Leucócitos Mononucleares/efeitos dos fármacos , Compostos de Rutênio/farmacologia , Adulto , Anexina A5/química , Antineoplásicos/farmacologia , Proliferação de Células , Fragmentação do DNA , Desenho de Fármacos , Humanos , Sistema Imunitário , Interleucina-2/metabolismo , Oligoelementos/química
7.
J Biosci ; 35(3): 371-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20826946

RESUMO

Ruthenium (III) complexes are increasingly attracting the interest of researchers due to their promising pharmacological properties. Recently, we reported that the cis-(dichloro)tetrammineruthenium (III) chloride compound has cytotoxic effects on murine sarcoma 180 (S-180) cells. In an effort to understand the mechanism responsible for their cytotoxicity, study we investigated the genotoxicity, cell cycle distribution and induction of apoptosis caused by cis- (dichloro) tetrammineruthenium (III) chloride in S-180 tumour cells. cis-(dichloro) tetrammineruthenium (III) chloride treatment induced significant DNA damage in S-180 cells, as detected by the alkaline comet assay. In the cell cycle analysis, cis-(dichloro) tetrammineruthenium (III) chloride caused an increase in the number of cells in G1 phase, accompanied by a decrease in the S and G2 phases after 24 h of treatment. In contrast, the cell cycle distribution of S-180 cells treated with cis-(dichloro) tetrammineruthenium (III) chloride for 48 h showed a concentration-dependent increase in the sub-G1 phase (indicating apoptosis), with a corresponding decrease in cells in the G1, S and G2 phases. In addition, cis-(dichloro) tetrammineruthenium(III) chloride treatment induced apoptosis in a time-dependent manner,as observed by the increased numbers of annexin V-positive cells. Taken together, these findings strongly demonstrate that DNA damage, cell cycle changes and apoptosis may correlate with the cytotoxic effects of cis-(dichloro) tetrammineruthenium (III) chloride on S-180 cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Dano ao DNA , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Camundongos , Compostos de Rutênio/farmacologia
8.
Arq. bras. oftalmol ; Arq. bras. oftalmol;78(2): 89-93, Mar-Apr/2015. graf
Artigo em Inglês | LILACS | ID: lil-744287

RESUMO

Purpose: To assess the cytotoxicity and genotoxicity of intravitreal adalimumab treatment in an animal experimental model using cytological and molecular techniques. Methods: Eighteen rabbits were randomly assigned to three groups: control, adalimumab treatment, and placebo. Cytotoxicity on retinal cells was evaluated using flow cytometry assays to determine the level of apoptosis and necrosis. Genotoxicity was evaluated by comet assays to assess DNA damage, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate expression of apoptosis-inducing caspases (8 and 3). Results: No cytotoxicity or genotoxicity was observed in any of the two treatment groups (adalimumab and placebo) following intravitreal administration compared with the control group. Flow cytometry analysis revealed that more than 90% of the cells were viable, and only a low proportion of retinal cells presented apoptotic (~10%) or necrotic (<1%) activity across all groups. Molecular damage was also low with a maximum of 6.4% DNA degradation observed in the comet assays. In addition, no increase in gene expression of apoptosis-inducing caspases was observed on retinal cells by qPCR in both the adalimumab and placebo groups compared with the control group. Conclusion: The use of adalimumab resulted in no detectable cytotoxicity or genotoxicity on retinal cells for up to 60 days upon administration. These results therefore indicate that adalimumab may be a safe option for intravitreal application to treat ocular inflammatory diseases in which TNF-α is involved. .


Objetivo: Acessar a citotoxicidade e genotoxicidade do tratamento intravítreo de adalimumabe em um modelo experimental animal utilizando técnicas citológicas e moleculares. Métodos: Dezoito coelhos foram aleatoriamente selecionados em três grupos: controle, tratamento intravítreo com adalimumabe e placebo. Os efeitos tóxicos nas células da retina foram avaliados através de ensaios de citometria de fluxo, para a determinação de atividade apoptótica e necrótica. A genotoxidade foi avaliada através de ensaios cometa para determinar danos ao DNA e através de PCR em tempo real para avaliar a expressão genética de caspases (8 e 3) promotoras de apoptose celular. Resultados: Não foram detectadas citotoxicidade e genotoxidade nos dois grupos de tratamento, adalimumabe e placebo, em comparação com o controle. A citometria de fluxo determinou que mais de 90% das células eram viáveis após o tratamento, e uma pequena quantidade de células da retina apresentaram apoptose (~10%) ou necrose (<1%) em todos os grupos. O dano molecular também foi baixo com uma degradação no DNA de no máximo 6,4% detectados nos ensaios cometa. Adicionalmente, não foram observados aumentos na expressão genética das caspases que induzem a apoptose através dos ensaios de PCR em tempo real. Conclusão: O tratamento intravítreo com adalimumabe não promoveu nenhuma citotoxicidade e genotoxicidade detectável em células da retina por até sessenta dias. Estes resultados, portanto, indicam que o adalimumabe pode ser uma opção segura para o tratamento de doenças oculares inflamatórias em que o TNFα está envolvido. .


Assuntos
Humanos , Infecções Relacionadas a Cateter/prevenção & controle , Infecção Hospitalar/prevenção & controle , Controle de Infecções/métodos , Sistemas Computadorizados de Registros Médicos , Vigilância da População/métodos , Infecções Urinárias/prevenção & controle , Infecções Relacionadas a Cateter/epidemiologia , Infecção Hospitalar/epidemiologia , Hospitais/estatística & dados numéricos , Distribuição de Poisson , Avaliação de Programas e Projetos de Saúde , Pennsylvania/epidemiologia , Análise de Regressão , Estudos Retrospectivos , Infecções Urinárias/epidemiologia , Infecções Urinárias/etiologia
9.
Toxicol In Vitro ; 24(6): 1562-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20600797

RESUMO

Ruthenium(III) complexes are increasingly attracting the interest of researchers due to their promising pharmacological properties. In the present study, we investigated the ability of cis-(dichloro)tetrammineruthenium(III) chloride to produce lethal effects in human chronic myelogenous leukemia K562 cells. The MTT tetrazolium reduction test and the trypan blue exclusion assay revealed that the IC(50) for the compound after 48 h of incubation with K562 cells was approximately 10.74 and 73.45 microM, respectively. Interestingly, it was observed that this compound exhibits mild cytotoxicity towards MRC-5 human fibroblast cells (IC(50)>383 microM). Flow cytometric analysis revealed that cis-(dichloro)tetrammineruthenium(III) chloride was capable of change cell cycle distribution since the percentage of cells in the G1, S and G2 phases decreased. In addition, treatment with this compound induced apoptotic cell death in K562 cells, demonstrated by increased DNA content in the sub-G1-peak and a significant increase in caspase-3 activity. Assay using cyclosporin A, an inhibitor of the mitochondrial permeability transition pore (MPT) showed that the preincubation of K562 cells with this inhibitor had not effect on cis-(dichloro)tetrammineruthenium(III) chloride induced caspase-3 activation. In summary, cis-(dichloro)tetrammineruthenium(III) chloride displayed a significant cytotoxic effect through cell cycle arrest and apoptotic induction in K562 cells, which suggests that cis-(dichloro)tetrammineruthenium(III) chloride might have therapeutic potential against leukemia.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Leucemia Eritroblástica Aguda/tratamento farmacológico , Compostos de Rutênio/farmacologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclosporina/farmacologia , Humanos , Células K562 , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patologia , Sais de Tetrazólio/metabolismo , Tiazóis/metabolismo , Azul Tripano/metabolismo , Ensaio Tumoral de Célula-Tronco
10.
Biol Trace Elem Res ; 128(3): 258-68, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19020813

RESUMO

Ruthenium complexes have attracted much attention as possible building blocks for new transition-metal-based antitumor agents. The present study examines the mitotoxic and clastogenic effects induced in the root tips of Allium cepa by cis-tetraammine(oxalato)ruthenium(III) dithionate {cis-[Ru(C(2)O(2))(NH(3))(4)](2)(S(2)O(6))} at different exposure durations and concentrations. Correlation tests were performed to determine the effects of the time of exposure and concentration of ruthenium complex on mitotic index (MI) and mitotic aberration index. A comparison of MI results of cis-[Ru(C(2)O(2))(NH(3))(4)](2)(S(2)O(6)) to those of lead nitrate reveals that the ruthenium complex demonstrates an average mitotic inhibition eightfold higher than lead, with the frequency of cellular abnormalities almost fourfold lower and mitotic aberration threefold lower. A. cepa root cells exposed to a range of ruthenium complex concentrations did not display significant clastogenic effects. Cis-tetraammine(oxalato)ruthenium(III) dithionate therefore exhibits a remarkable capacity to inhibit mitosis, perhaps by inhibiting DNA synthesis or blocking the cell cycle in the G2 phase. Further investigation of the mechanisms of action of this ruthenium complex will be important to define its clinical potential and to contribute to a novel and rational approach to developing a new metal-based drug with antitumor properties complementary to those exhibited by the drugs already in clinical use.


Assuntos
Allium/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Aberrações Cromossômicas/efeitos dos fármacos , Meristema/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Raízes de Plantas/efeitos dos fármacos , Compostos de Rutênio/farmacologia , Allium/citologia , Allium/genética , Relação Dose-Resposta a Droga , Chumbo/farmacologia , Meristema/citologia , Meristema/genética , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/estatística & dados numéricos , Mitógenos/farmacologia , Índice Mitótico , Nitratos/farmacologia , Raízes de Plantas/citologia , Raízes de Plantas/genética
11.
Biol Trace Elem Res ; 130(3): 249-61, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19214395

RESUMO

Chemotherapeutic agents play an important role in cancer treatment mostly due their systemic action on human organism allowing access to liquid tumors and even metastases. Among these drugs, ruthenium compounds have been showing promising results to treat tumors and represent an important development of new antitumor therapy. This study presents the evaluation of cis-(dichloro)tetraammineruthenium(III) chloride, cis-[RuCl(2)(NH(3))(4)]Cl, genotoxic effects using human peripheral blood lymphocytes cultured in vitro. Mitotic index (MI), chromosome aberrations (CA), and DNA damage using the comet assay were analyzed. MI in human peripheral blood lymphocyte cultures treated with 1, 10, 100, and 1,000 microg mL(-1) cis-[RuCl(2)(NH(3))(4)]Cl were 5.9%, 4.6%, 3.9%, and 0%, respectively. Doxorubicin chloridate was used as the positive control. CA derived from 1, 10, and 100 microg mL(-1) concentrations were defined as spontaneous when compared with the negative control, and at the concentration of 1,000 microg mL(-1), the cell cycle was inhibited (IM = 0%). Results obtained for the comet assay using cis-[RuCl(2)(NH(3))(4)]Cl suggest that this compound has no genotoxic activity against cultured human peripheral blood lymphocytes.


Assuntos
Antineoplásicos/toxicidade , Linfócitos/efeitos dos fármacos , Testes de Mutagenicidade , Compostos de Rutênio/toxicidade , Adulto , Antineoplásicos/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Células Cultivadas , Aberrações Cromossômicas/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Humanos , Linfócitos/citologia , Metáfase/efeitos dos fármacos , Índice Mitótico , Compostos de Rutênio/administração & dosagem , Adulto Jovem
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