RESUMO
The metal alloys used in dentistry are made mainly of nickel (Ni), titanium (Ti), and other elements such as molybdenum (Mo), zirconium (Zr), iron (Fe), tin (Sn), chrome (Cr), carbon (C), copper (Cu) and niobium (Nb) which can release metal ions in unstable environments. The aim of this work was determine the salivary pH before and during orthodontic treatment; evaluate the release of metal ions, mainly Ni and Ti, in urine and saliva using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES); and evaluate the corrosion using Scanning Electronic Microscopy (SEM). In this study, we selected 35 individuals under orthodontic treatment, from whom saliva and urine samples were collected in 3 stages: (a) basal, (b) at 3 and (c) 6 months after the placement of the fixed appliances. SEM analyzed the Ni-Ti (0.016â³) and stainless steel (SS) (0.016 × 0.022â³) archs after 1 month of being in contact with the oral cavity. Statistical analysis was performed with Stata using the ANOVA model of repeated measures with a p < 0.05. A statistically significant difference in the concentration of Ni in saliva were found between 3 and 6 months of intervention and Ti in urine was found 3 and 6 months.
Assuntos
Ligas Dentárias/uso terapêutico , Níquel/uso terapêutico , Saliva/efeitos dos fármacos , Titânio/uso terapêutico , Adolescente , Ligas/química , Ligas/uso terapêutico , Criança , Cobre/uso terapêutico , Cobre/urina , Ligas Dentárias/efeitos adversos , Feminino , Humanos , Íons/urina , Ferro/uso terapêutico , Ferro/urina , Masculino , Molibdênio/uso terapêutico , Molibdênio/urina , Níquel/efeitos adversos , Níquel/urina , Nióbio/uso terapêutico , Nióbio/urina , Aço Inoxidável/química , Titânio/efeitos adversos , Titânio/urina , Zircônio/uso terapêutico , Zircônio/urinaRESUMO
Trabectedin (Yondelis; ET-743) is a potent anticancer drug that binds to DNA by forming a covalent bond with a guanine in one strand and one or more hydrogen bonds with the opposite strand. Using a fluorescence-based melting assay, we show that one single trabectedin-DNA adduct increases the thermal stability of the double helix by >20 degrees C. As deduced from the analysis of phosphorylated H2AX and Rad51 foci, we observed that clinically relevant doses of trabectedin induce the formation of DNA double-strand breaks in human cells and activate homologous recombination repair in a manner similar to that evoked by the DNA interstrand cross-linking agent mitomycin C (MMC). Because one important characteristic of this drug is its marked cytotoxicity on cells lacking a functional Fanconi anemia (FA) pathway, we compared the response of different subtypes of FA cells to MMC and trabectedin. Our data clearly show that human cells with mutations in FANCA, FANCC, FANCF, FANCG, or FANCD1 genes are highly sensitive to both MMC and trabectedin. However, in marked contrast to MMC, trabectedin does not induce any significant accumulation of FA cells in G2-M. The critical relevance of FA proteins in the response of human cells to trabectedin reported herein, together with observations showing the role of the FA pathway in cancer suppression, strongly suggest that screening for mutations in FA genes may facilitate the identification of tumors displaying enhanced sensitivity to this novel anticancer drug.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Dioxóis/farmacologia , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Tetra-Hidroisoquinolinas/farmacologia , Ciclo Celular , DNA/genética , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Relação Dose-Resposta a Droga , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Humanos , Mitomicina/farmacologia , Fatores de Tempo , TrabectedinaRESUMO
The marine natural product thiocoraline A displayed approximately equal cytotoxic activity at nanomolar concentrations in a panel of 12 human cancer cell lines. X-ray diffraction analyses of orthorhombic crystals of this DNA-binding drug revealed arrays of docked pairs of staple-shaped molecules in which one pendent hydroxyquinoline chromophore from each cysteine-rich molecule appears intercalated between the two chromophores of a facing molecule. This arrangement is in contrast to the proposed mode of binding to DNA that shows the two drug chromophores clamping two stacked base pairs, in agreement with the nearest-neighbor exclusion principle. Proof of DNA sequence recognition was obtained from both classical DNase I footprinting experiments and determination of the melting temperatures of several custom-designed fluorescently labeled oligonucleotides. A rationale for the DNA-binding behavior was gained when models of thiocoraline clamping a central step embedded in several octanucleotides were built and studied by means of unrestrained molecular dynamics simulations in aqueous solution.
Assuntos
Antineoplásicos/farmacologia , DNA/metabolismo , Depsipeptídeos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Cristalografia por Raios X , Pegada de DNA , Depsipeptídeos/química , Depsipeptídeos/metabolismo , Humanos , EstereoisomerismoRESUMO
Zalypsis is a new synthetic alkaloid tetrahydroisoquinoline antibiotic that has a reactive carbinolamine group. This functionality can lead to the formation of a covalent bond with the amino group of selected guanines in the DNA double helix, both in the absence and in the presence of methylated cytosines. The resulting complex is additionally stabilized by the establishment of one or more hydrogen bonds with adjacent nucleotides in the opposite strand as well as by van der Waals interactions within the minor groove. Fluorescence-based thermal denaturation experiments demonstrated that the most favorable DNA triplets for covalent adduct formation are AGG, GGC, AGC, CGG and TGG, and these preferences could be rationalized on the basis of molecular modeling results. Zalypsis-DNA adducts eventually give rise to double-strand breaks, triggering S-phase accumulation and apoptotic cell death. The potent cytotoxic activity of Zalypsis was ascertained in a 24 cell line panel. The mean IC(50) value was 7nM and leukemia and stomach tumor cell lines were amongst the most sensitive. Zalypsis administration in four murine xenograft models of human cancer demonstrates significant tumor growth inhibition that is highest in the Hs746t gastric cancer cell line with no weight loss of treated animals. Taken together, these results indicate that the potent antitumor activity of Zalypsis supports its current development in the clinic as an anticancer agent.