RESUMO
Highly active antiretroviral therapy (HAART) regimens are based on the use of nucleoside reverse transcriptase inhibitors (NRTIs), which are the main drugs used by patients infected with the human immunodeficiency virus (HIV). The use of NRTIs combinations has afforded clear clinical benefits to patients undergoing HAART. However, the combination of two NRTIs may increase the risk of genomic instability in comparison with the drugs administered individually. We analyzed the ability of zidovudine (AZT) and lamivudine (3TC), and the combination AZT +3TC to induce complex genomic alterations using the cytokinesis-block micronucleus (CBMN) assay in Chinese hamster ovary (CHO)-K1 cells. The 24-h cell treatment with individual NRTIs showed that AZT increased micronucleus frequencies and nucleoplasmic bridges (NPBs). No significant differences were observed for any parameters investigated after exposure of CHO-K1 cells to 3TC. The combination AZT +3TC significantly increased micronucleus frequencies. Analysis of interaction between these drugs suggested that antagonism occurs in all AZT +3TC concentrations. These results highlight the importance to investigate the genotoxic profile of NRTIs to develop safer intervention strategies in antiretroviral treatment protocols.
Assuntos
Fármacos Anti-HIV/toxicidade , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Dano ao DNA , Lamivudina/toxicidade , Inibidores da Transcriptase Reversa/toxicidade , Zidovudina/toxicidade , Animais , Células CHO , Cricetulus , Lamivudina/administração & dosagem , Mutagênese , Mutação , Zidovudina/administração & dosagemRESUMO
Natural radiation of geological origin is a common phenomenon in Brazil, a country where radioactive agents such as uranium may be often found. As an unstable atom, uranium undergoes radioactive decay with the generation of a series of decay by-products, including radon, which may be highly genotoxic and trigger several pathological processes, among which cancer. Because it is a gas, radon may move freely between cracks and gaps in the ground, seeping upwards into the buildings and in the environment. In this study, two Drosophila melanogaster Meigen (Diptera, Drosophilidae) strains called Oregon-R and Wild (collected in a non-radioactive environment) were exposed to atmospheric radiation in the Lajes Pintadas city, in the semiarid zone of northeastern Brazil. After six days of environmental exposure, the organisms presented genetic damage significantly higher than that of the negative control group. The genotoxic effects observed reinforce the findings of other studies carried out in the same region, which warn about the environmental risks related to natural radioactivity occurrence. The results also validate the use of the Comet assay in hemocytes of D. melanogaster as a sensitive test to detect genotoxicity caused by natural radiation, and the use of a recently collected D. melanogaster strain in the environmental of radon.
Assuntos
Radiação de Fundo/efeitos adversos , Ensaio Cometa/métodos , Dano ao DNA , Drosophila melanogaster/efeitos da radiação , Exposição Ambiental , Radônio/toxicidade , Animais , Brasil , Clima Desértico , Drosophila melanogaster/genética , Hemócitos/química , Sensibilidade e Especificidade , Urânio/toxicidadeRESUMO
Commonly used guidelines for the management of human immunodeficiency virus (HIV) infection (highly active antiretroviral therapy, HAART) include drug combinations such as tenofovir disoproxil fumarate (TDF) + lamivudine (3TC) and combivir [zidovudine (AZT) + 3TC] + efavirenz (EFV). These combinations may enhance the genotoxic effects induced by such drugs individually, since the therapy requires lifelong adherence and the drugs have unknown effects during treatment. Thus, the evaluation of the benefits and risks of HAART is of great importance. In order to assess the cytotoxic and genotoxic potential of three concentrations of each of the antiretroviral combinations TDF + 3TC (800 + 400, 1600 + 800, and 3200 + 1600 mg/kg body weight, BW) and combivir + EFV (200 + 100 + 400, 400 + 200 + 800, and 800 + 400 + 1600 mg/kg BW) after two exposure periods (24 h and 48 h), in the present study the in vivo comet assay (single-cell gel electrophoresis) and the mouse bone marrow micronucleus test were used. Neither TDF + 3TC nor combivir + EFV induced DNA damage at any concentrations tested after 24 h or 48 h using the comet assay. After 24 h, both combinations increased the micronucleus frequency at all concentrations tested. After 48 h, combivir + EFV increased the micronucleated polychromatic erythrocyte (MNPCE) frequency at the two highest concentrations tested. Polychromatic erythrocytes (PCE)/normochromatic erythrocytes (NCE) ratio was high for both combinations, suggesting that they can be mitogenic. Since genotoxicity may be related to carcinogenesis, it is necessary to conduct further studies to verify the long-term mutagenic effects of these drugs.
Assuntos
Quimioterapia Combinada/efeitos adversos , Lamivudina/administração & dosagem , Tenofovir/administração & dosagem , Zidovudina/administração & dosagem , Animais , Terapia Antirretroviral de Alta Atividade , Medula Óssea/efeitos dos fármacos , Ensaio Cometa , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Lamivudina/efeitos adversos , Camundongos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Tenofovir/efeitos adversos , Zidovudina/efeitos adversosRESUMO
Fruits and derivatives, such as juices, are complex mixtures of chemicals, some of which may have mutagenic and/or carcinogenic potential, while others may have antimutagenic and/or anticancer activities. The modulating effects of honey-sweetened cashew apple nectar (HSCAN), on somatic mutation and recombination induced by ethyl methanesulfonate (EMS) and mitomycin C (MMC) were evaluated with the wing spot test in Drosophila melanogaster using co- and post-treatment protocols. Additionally, the antimutagenic activity of two HSCAN components, cashew apple pulp and honey, in MMC-induced DNA damage was also investigated. HSCAN reduced the mutagenic activity of both EMS and MMC in the co-treatment protocol, but had a co-mutagenic effect when post-administered. Similar results were also observed with honey on MMC mutagenic activity. Cashew apple pulp was effective in exerting protective or enhancing effects on the MMC mutagenicity, depending on the administration protocol and concentration used. Overall, these results indicate that HSCAN, cashew apple and honey seem capable of modulating not only the events that precede the induced DNA damages, but also the Drosophila DNA repair processes involved in the correction of EMS and MMC-induced damages.
RESUMO
In order to assess the safety of the carbon nanotubes to human health and the environment, we investigated the potential toxicity and ability of multi-walled carbon nanotubes (NT), to induce DNA damage by employing the Allium cepa genotoxicity/mutagenicity test and the Somatic Mutation and Recombination Test (SMART) in the fruitfly, Drosophila melanogaster. The results demonstrated that NT did not significantly induce genotoxic or mutagenic effects in the Allium cepa test. All concentrations evaluated in the SMART assay showed survival rates higher than 90percent, indicating the absence of chronic toxicity for NT. Furthermore, the various treatments showed no significant increase in the NT mutation and recombination frequencies in mwh/flr(3) genotype compared to respective negative controls, demonstrating the absence of DNA damage caused by NT.
Assuntos
Drosophila melanogaster/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Cebolas/efeitos dos fármacos , Animais , Dano ao DNA/efeitos dos fármacos , Testes de Mutagenicidade , Mutação/efeitos dos fármacos , Nanotubos de Carbono/química , Nanotubos de Carbono/ultraestrutura , Recombinação Genética/efeitos dos fármacos , Asas de Animais/efeitos dos fármacosRESUMO
The simultaneous treatment with the cross-linking agent cisplatin, the radiomimetic antitumoral drug bleomycin, and the anti-metabolite drug 5-fluorouracil has been used as a regimen to treat patients with squamous cell carcinoma of the head and neck. Considering that these drugs interact directly with DNA, one of the important late-occurring complications from treatment of primary malignancies is the therapy-related secondary cancers as a result of the genotoxic activity of the drugs on normal cells. In this sense, the genotoxicity of this combination was evaluated using the wing somatic mutation and recombination test in Drosophila melanogaster. The mutant spots observed in marker-heterozygous and balancer-heterozygous flies were compared in order to quantitatively and qualitatively estimate the genotoxic effect of these drugs. Cisplatin (0.003 and 0.006mM), bleomycin (0.005 and 0.01mM), and both combinations preferentially induced recombinational events, while mutation is the major event regarding the genetic toxicity of 5-fluorouracil (0.025 and 0.05mM). The combination of these drugs produced synergistic and antagonistic genotoxic effects, depending on the concentrations used, which could impose a higher risk of secondary effects associated with their genotoxic effects, emphasizing the importance of long-term monitoring in patients being treated with these drugs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Bleomicina/toxicidade , Cisplatino/toxicidade , Fluoruracila/toxicidade , Mutagênicos/toxicidade , Animais , Cisplatino/antagonistas & inibidores , Dano ao DNA , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Testes de MutagenicidadeRESUMO
Fluoroquinolones are widely used in human and in veterinary medicine due to their broad-spectrum antibacterial activity. They act by inhibiting type II DNA topoisomerases (gyrase and topoisomerase IV). Because of the sequence homology between prokaryotic and eukaryotic topoisomerases II, fluoroquinolones can pose a hazard to eukaryotic cells. However, published information concerning the genotoxic profiles of these drugs in vivo is sparse and inconsistent. We have assessed the activities of three fluoroquinolones, ciprofloxacin, enrofloxacin and norfloxacin, in the Drosophila melanogaster Somatic Mutation and Recombination Test (SMART) and measured their mutagenic and recombinagenic potentials. Norfloxacin was non-genotoxic. Ciprofloxacin and enrofloxacin induced significant increases in spot frequencies in trans-heterozygous flies. To test the roles of somatic recombination and mutation in the observed genotoxicity, balancer-heterozygous flies were also analyzed. Ciprofloxacin and enrofloxacin were preferential inducers of homologous recombination in proliferative cells, an event linked to loss of heterozygosity.
Assuntos
Antibacterianos/toxicidade , Drosophila melanogaster/genética , Fluoroquinolonas/toxicidade , Recombinação Homóloga/efeitos dos fármacos , Mutagênicos/toxicidade , Animais , Testes de Mutagenicidade/métodosRESUMO
The somatic mutation and recombination test in Drosophila melanogaster was applied to analyze the mutagenic and recombinagenic activity of the chemotherapeutic drugs cisplatin, paclitaxel, and 5-fluorouracil, comparing the effects observed in combinatory treatments with those observed in single administrations. The results obtained in two different genotypes allowed to quantitatively and qualitatively estimate the contribution of genotoxic effects. The results obtained with the individual drug treatments showed that cisplatin and 5-fluorouracil were genotoxic, being able to increase the frequency of total spots on both genotypes. While cisplatin preferentially induced DNA damage of recombinational origin, all the damages induced by 5-fluorouracil were caused by gene and/or chromosome mutations, and the aneuploidogenic compound paclitaxel was not genotoxic. The combination of these drugs does not exert a synergist genotoxic effect in both genotypes compared to the single-agent administration. Instead, it was observed a modification in the proportion of mutation and recombination to the final genotoxicity observed. The antiproliferative activity of PAC could be responsible for the non-synergic genotoxic effect observed. Based on our results it is possible to suggest that cisplatin/paclitaxel/5-fluorouracil treatment regimen cannot impose a higher risk of the development of genotoxicity-associated secondary tumors in comparison to their individual applications.
Assuntos
Antineoplásicos/toxicidade , Drosophila/genética , Mutagênicos/toxicidade , Mutação/efeitos dos fármacos , Recombinação Genética/efeitos dos fármacos , Asas de Animais/efeitos dos fármacos , Animais , Cisplatino/toxicidade , Cruzamentos Genéticos , Drosophila/citologia , Drosophila/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Fluoruracila/toxicidade , Marcadores Genéticos/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Masculino , Testes de Mutagenicidade/métodos , Mutação/genética , Paclitaxel/toxicidade , Asas de Animais/citologia , Asas de Animais/crescimento & desenvolvimentoRESUMO
IMPORTANCE OF THE FIELD: The nucleoside reverse transcriptase inhibitors (NRTIs) are used in antiretroviral therapy worldwide for the treatment of HIV infections. These drugs act by blocking reverse transcriptase enzyme activity, causing pro-viral DNA chain termination. As a consequence, NRTIs could cause genomic instability and loss of heterozygosity. AREAS COVERED IN THIS REVIEW: This review highlights the toxic and genotoxic effects of NRTIs, particularly lamivudine (3TC) and stavudine (d4T) analogues. In addition, a battery of short-term in vitro and in vivo systems are described to explain the potential genotoxic effects of these NRTIs as a single drug or a complexity of highly active antiretroviral therapy. WHAT THE READER WILL GAIN: The readers will gain an understanding of a secondary effect that could be induced by 3TC and d4T treatments. TAKE HOME MESSAGE: Considering that AIDS has become a chronic disease, more comprehensive toxic genetic studies are needed, with particular attention to the genetic alterations induced by NRTIs. These alterations play a primary role in carcinogenesis and are also involved in secondary and subsequent steps of carcinogenesis.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Aberrações Cromossômicas/efeitos dos fármacos , Lamivudina/efeitos adversos , Mutação , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Adulto , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Criança , Ensaios Clínicos como Assunto , Cricetinae , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Haplorrinos , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Lamivudina/toxicidade , Camundongos , Testes de Mutagenicidade , Ratos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/toxicidade , Estavudina/administração & dosagem , Estavudina/farmacocinética , Estavudina/toxicidadeRESUMO
Recent studies have added paclitaxel (PAC) to traditional cisplatin (CIS) regimen to treat squamous cell carcinoma of the head and neck. The target of these antineoplastic agents is nuclear DNA for CIS and microtubules for PAC, although it is not restricted to malignant cells. In this study, the genotoxicity of the combined treatment of PAC and CIS was investigated using the standard version of the wing Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. Quantitative and qualitative genotoxic effects of these compounds were estimated by comparing wing spot frequencies in marker-heterozygous to balancer-heterozygous flies. Two different concentrations of PAC (0.0025 and 0.005mM) and CIS (0.025 and 0.05mM) as well as combinations of them were employed. The results demonstrated that the spindle poison PAC alone was not genotoxic in this test system, while CIS was able to induce a high incidence of DNA damage in both genotypes, mainly related to somatic recombination. The data obtained for the combined treatments showed that its genotoxicity varied with the concentrations used. In small concentrations the number of total spots induced by combination was reduced in relation to CIS 0.025mM just for marker-heterozygous flies, showing that somatic recombination was the prevalent event involved. At higher concentrations the combined treatment showed significant reductions in the frequencies of large single spots, for both genotypes, and twin spots for marker-heterozygous flies, but did not significantly reduce the total spots frequency in either genotype. The data suggest that aneugenic activity of PAC could be responsible for the reduction in the genotoxicity of CIS.