Exposição prolongada aos quimioterápicos 5-fluorouracil e metotrexato em concentrações ambientalmente relevantes: Avaliação da toxicidade testicular e danos ao DNA de ratos
Data
2022-01-24
Autores
Medeiros, Paloma da Cunha de 
Orientadores
Perobelli, Juliana Elaine
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Drogas antineoplásicas, utilizadas para tratamento de pacientes com câncer, atuam na prevenção do crescimento do tumor por meio do controle das divisões celulares. Um dos mecanismos de ação ocorre por interação com o DNA das células cancerígenas, causando alterações metabólicas e morfológicas nas mesmas, levando à morte celular. No entanto, não atuam de maneira seletiva, acarretando efeitos colaterais indesejáveis em células saudáveis. Sabe-se que o consumo dessa classe de medicamentos tem aumentado em todo o mundo devido às crescentes taxas de incidência de câncer na população, ao diagnóstico precoce e ao uso combinado de medicamentos (poliquimioterapia). O 5-fluorouracil (5-FU) e o metotrexato (MTX) estão entre os medicamentos antineoplásicos mais consumidos no mundo. Depois de consumidos eles são excretados pelas fezes e/ou urina em uma mistura de compostos e metabólitos. Dessa forma, entram no ambiente aquático por meio de estações de tratamento de efluentes, que ainda apresentam baixa eficiência na remoção desses fármacos, podendo ser detectados constantemente no ambiente. Por isso, essas drogas são consideradas poluentes emergentes, sendo encontradas em concentrações que vão de ng/L a mg/L em fluxos de água. O presente estudo visou investigar o potencial impacto da exposição prolongada a esses quimioterápicos em concentrações ambientalmente relevantes. Ratos Wistar machos (70 dias de idade) foram distribuídos em 4 grupos (n= 10/grupo): controle, que recebeu apenas veículo; MTX que recebeu metotrexato na concentração 10 ng/L na água de beber; 5-FU que recebeu 5-fluorouracil na concentração 10 ng/L na água de beber; e o MTX + 5-FU que recebeu a associação de metotrexato e 5-fluorouracil, na concentração de 10 ng/L cada, na água de beber. O período de tratamento compreendeu o DPN (dia pós-natal) 70 ao 160, quando os animais foram eutanasiados para avaliação de toxicidade testicular (análises histomorfométricas, dano oxidativo e alterações na sinalização endócrina) e danos ao DNA (citotoxicidade, genotoxicidade e mutagenicidade). Nas condições experimentais apresentadas o metotrexato isolado aparenta ser o quimioterápico com mais efeitos deletérios aos órgãos alvos deste estudo. No entanto, ambos fármacos causaram efeitos citotóxicos nos órgãos reprodutivos e acessórios, bem como, danos genéticos a ratos expostos prolongadamente a essas substâncias, ainda que em concentrações baixas.
Antineoplastic drugs, used to treat cancer, act to prevent tumor growth by controlling cell divisions. They may interact with the DNA of cancer cells, causing metabolic and morphological changes, leading to cell death. However, they do not act selectively, resulting in undesirable side effects in healthy cells. It is known that the consumption of this class of drugs has increased worldwide due to the increasing rates of cancer incidence in the population, the early diagnosis, and the use of medications in combination (polichemotherapy). 5-fluorouracil (5-FU) and methotrexate (MTX) are among the most widely consumed antineoplastic drugs in the world. After consumed they are excreted by feces and/ or urine in a mixture of compounds and metabolites. In this way, they enter the aquatic environment through effluent treatment plants, which still have low efficiency in drug removal, and it can be constantly detected in the environment. Therefore, these drugs are known as emerging pollutants, being found in concentrations ranging from ng/L to mg/L in water flows. The present study aimed to investigate the potential impact of extended exposure to these antineoplastic drugs in environmentally relevant concentrations. Male Wistar rats (70 days old) were distributed into 4 groups (n = 10 / group): control, received only vehicle; MTX received methotrexate at 10 ng/L in drinking water; 5-FU received 5-fluorouracil at 10 ng/L in drinking water; and MTX + 5FU, received the combination of methotrexate and 5-fluorouracil at a concentration of 10 ng/L each in drinking water. The treatment period was from post-natal day (PND)70 to PND160, when the animals were euthanized for evaluation of testicular toxicity (histomorphometric analysis, oxidative damage and changes in endocrine signaling) and DNA damage (cytotoxicity, genotoxicity and mutagenicity). In these experimental conditions, methotrexate isolated seems to be the chemotherapic that caused more damage to target tissues in this study. However, both drugs caused cytotoxic effects in the reproductive and accessory tissues, as well, genetic damage to rats prolonged exposed to these compounds even at environmental concentrations
Antineoplastic drugs, used to treat cancer, act to prevent tumor growth by controlling cell divisions. They may interact with the DNA of cancer cells, causing metabolic and morphological changes, leading to cell death. However, they do not act selectively, resulting in undesirable side effects in healthy cells. It is known that the consumption of this class of drugs has increased worldwide due to the increasing rates of cancer incidence in the population, the early diagnosis, and the use of medications in combination (polichemotherapy). 5-fluorouracil (5-FU) and methotrexate (MTX) are among the most widely consumed antineoplastic drugs in the world. After consumed they are excreted by feces and/ or urine in a mixture of compounds and metabolites. In this way, they enter the aquatic environment through effluent treatment plants, which still have low efficiency in drug removal, and it can be constantly detected in the environment. Therefore, these drugs are known as emerging pollutants, being found in concentrations ranging from ng/L to mg/L in water flows. The present study aimed to investigate the potential impact of extended exposure to these antineoplastic drugs in environmentally relevant concentrations. Male Wistar rats (70 days old) were distributed into 4 groups (n = 10 / group): control, received only vehicle; MTX received methotrexate at 10 ng/L in drinking water; 5-FU received 5-fluorouracil at 10 ng/L in drinking water; and MTX + 5FU, received the combination of methotrexate and 5-fluorouracil at a concentration of 10 ng/L each in drinking water. The treatment period was from post-natal day (PND)70 to PND160, when the animals were euthanized for evaluation of testicular toxicity (histomorphometric analysis, oxidative damage and changes in endocrine signaling) and DNA damage (cytotoxicity, genotoxicity and mutagenicity). In these experimental conditions, methotrexate isolated seems to be the chemotherapic that caused more damage to target tissues in this study. However, both drugs caused cytotoxic effects in the reproductive and accessory tissues, as well, genetic damage to rats prolonged exposed to these compounds even at environmental concentrations
Descrição
Citação
MEDEIROS, Paloma da Cunha de. Exposição prolongada aos quimioterápicos 5-fluorouracil e metotrexato em concentrações ambientalmente relevantes: Avaliação da toxicidade testicular e danos ao DNA de ratos. 2022. 96 f. Dissertação (Mestrado Interdisciplinar em Ciências da Saúde) - Instituto de Saúde e Sociedade, Universidade Federal de São Paulo, Santos, 2022.