Kátia da Conceição Machado, Jurandy do Nascimento Silva, Débora Caroline do Nascimento Rodrigues, Stefânia Neiva Lavorato, João Marcelo de Castro E Sousa, Ana Amélia de Carvalho Melo-Cavalcante, Patrícia Canteri de Souza, Paulo César Meletti, Diego Sousa Moura, José Roberto de Oliveira Ferreira, Cesar Koppe Grisolia, Ricardo José Alves, Paulo Michel Pinheiro Ferreira
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引用次数: 0
Abstract
Non-clinical steps for development, validation and biosafety of new medicines and products comprises studies on cells, proteins, and animals. Herein, we evaluated the toxic activity of antitumoral 2-chloro-N-arylacetamides on eukaryotic dividing cells and animal replacement models. Firstly, the cytotoxicity of chloro (compound 2), bromo (compound 3) and nitro (compound 4) acetamides was analyzed by fluorescent assays in fibroblasts. Next, toxicity was evaluated on Allium cepa meristematic cells and 48h-living Artemia salina larvae. Finally, embryos of Danio rerio (zebrafish) were exposed to the compound 2 (0.14 - 7.2 μg/mL) for 120 h exposure. All arylacetamides were cytotoxic on murine and human fibroblasts, with IC50 values ranging from 1.2 μg/mL (5.6 µM = compound 4 on L-929) to 4.9 μg/mL (24 µM = compound 2 on MRC-5 cells), respectively, and inhibited root growth from 10 to 100 µg/mL, corroborated by mitotic index reduction and cell cycle arrest in interphase (p < 0.05) without clastogenic injuries. Compound 2 showed time- and concentration-dependent killing effects on zebrafish embryos. Its 24 h-acute toxicity at higher concentrations (1.93 and 7.2 μg/mL with 90% and 100% death) corroborated toxicity on aquatic A. salina organisms. After 96 h exposure at 0.52 μg/mL (2.55 µM), almost 100% of the embryos showed more than one lethal/sublethal morphological abnormality (p < 0.05). Then, all arylacetamides showed unspecific toxic effects, mainly the halogenated electrophile chloroacetamide. They present strong antimitotic action on vertebrate and vegetal cells, although such antiproliferative activity does not seem to be directly related to chromosomal damage inductions.
期刊介绍:
Drug and Chemical Toxicology publishes full-length research papers, review articles and short communications that encompass a broad spectrum of toxicological data surrounding risk assessment and harmful exposure. Manuscripts are considered according to their relevance to the journal.
Topics include both descriptive and mechanics research that illustrates the risk assessment implications of exposure to toxic agents. Examples of suitable topics include toxicological studies, which are structural examinations on the effects of dose, metabolism, and statistical or mechanism-based approaches to risk assessment. New findings and methods, along with safety evaluations, are also acceptable. Special issues may be reserved to publish symposium summaries, reviews in toxicology, and overviews of the practical interpretation and application of toxicological data.