ABSTRACT
Casiopeinas® are a group of newly synthesized drugs designed to treat cancer. These copper (Cu) complexes exhibit cytostatic, cytotoxic, genotoxic, and antineoplastic activities through different mechanisms of action. To evaluate the influence of these compounds, some in vivo studies were performed using predominantly somatic cells. The aim of the present study was to examine the cytotoxic and genotoxic actions of Casiopeina III-Ea (Cas III-Ea) in somatic as well as germ cells of Drosophila melanogaster. For cytotoxicity, the productivity and some morphometric parameters were measured and genotoxicity was assessed by means of the somatic mutation and recombination test assay in the wing. For this purpose, second-instar larvae of the Canton-S strain were treated with different concentrations of Cas III-Ea. The emerged adults were weighed, the area of the wings determined, and the number of trichomes of the region C' counted. The productivity of treated males was measured by a brood method to monitor the influence of Cas III-Ea on spermatozoa, meiotic stage cells, and spermatogonia. For genotoxicity, mwh + /+ flr3 larvae 48 hr age were chronically treated within the same concentration range. Results indicated that Cas III-Ea at all concentrations tested significantly increased the productivity per couple in Brood III (spermatids) while at 1 mM a marked elevation was noted in the three broods tested. In contrast, the weight and size of individuals as well as the size and number of cells in the wing were decreased significantly. Data suggest that Cas III-Ea is a weak genotoxic but selective mutagen. Failure to obtain a dose-related genotoxic response suggests that one of the preferred mechanisms of action of Cas III-Ea is to induce apoptosis.
Subject(s)
Antineoplastic Agents/toxicity , Coordination Complexes/toxicity , Phenanthrolines/toxicity , Animals , Drosophila melanogaster/drug effects , Female , Germ Cells/drug effects , Male , Mutagenicity Tests , Wings, Animal/drug effectsABSTRACT
The present study evaluates the superoxide dismutase (SOD) and catalase (CAT) activities in a wild strain of Drosophila melanogaster and the genotoxic potential induced by Cas II-gly (a new antineoplastic drug) using the somatic mutation and recombination test. Larvae 48h old were treated with Cas II-gly in a range of 0-1.5mM and aliquot were taken every 24h to have individuals treated for 24, 48, 72h and adulthood as well. A dose-dependent toxicity and a significant increase in SOD and CAT activities were found after a 24 and 48h treatment with 0.5-1.5mM concentrations. The comparison of the effect in enzymes with mutation indicated a positive correlation with increased genetic damage, after 24 and 48h of exposure for all concentrations tested. The addition of the genetic damage induced in each exposure time showed a significant effect, but only the small single spots had a concentration-related increase.
Subject(s)
Antineoplastic Agents/toxicity , Chelating Agents/toxicity , Copper/metabolism , Mutagens/toxicity , Organometallic Compounds/toxicity , Oxidative Stress/drug effects , Animals , Catalase/metabolism , Dose-Response Relationship, Drug , Drosophila melanogaster/drug effects , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Female , Lethal Dose 50 , Lipid Peroxidation/drug effects , Lipid Peroxidation/genetics , Male , Oxidative Stress/genetics , Recombination, Genetic/drug effects , Superoxide Dismutase/metabolism , Wings, Animal/drug effectsABSTRACT
New compounds with antituberculosis activity and their combination with classic drugs have been evaluated to determine possible interactions and antagonism. The aim of this study was to evaluate the in vitro activity of Casiopeínas® copper-based compounds (CasIIIia, CasIIIEa, and CasIIgly) alone and combined with isoniazid (INH), rifampicin, or ethambutol (EMB) against resistant and susceptible Mycobacterium tuberculosis. Seventeen clinical M. tuberculosis isolates (5 multi-drug resistant and 2 resistant to INH and/or EMB) were subjected to determination of the minimal inhibitory concentration (MIC) by the resazurin microtiter assay and combination assessment by the resazurin drug combination microtiter assay. The Casiopeínas® alone showed a remarkable effect against resistant isolates with MIC values from 0.78 to 12.50 µg/ml. Furthermore, a synergistic effect mainly with EMB is shown for both resistant and susceptible clinical isolates. Casiopeínas® are promising candidates for future investigation into the development of antituberculosis drugs, being one of the first examples of essential metal-based drugs used in this field.
Subject(s)
Antitubercular Agents/pharmacology , Coordination Complexes/pharmacology , Copper/chemistry , Mycobacterium tuberculosis/drug effects , Tuberculosis/microbiology , Antitubercular Agents/chemistry , Antitubercular Agents/therapeutic use , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Drug Resistance, Bacterial/drug effects , Drug Synergism , Ethambutol/pharmacology , Ethambutol/therapeutic use , Humans , Isoniazid/pharmacology , Isoniazid/therapeutic use , Macrophages/cytology , Macrophages/drug effects , Macrophages/microbiology , Microbial Sensitivity Tests , Mycobacterium tuberculosis/isolation & purification , Rifampin/pharmacology , Rifampin/therapeutic use , Tuberculosis/drug therapyABSTRACT
Casiopeinas is the generic name of a group of coordination complexes with a central copper atom bound to organic ligands, designed to be an alternative to cancer therapy. Indeed, some of these compounds can reduce implanted tumors in mice. Casiopeinas were expressly designed to interact with the genetic material, so the aim of the present work is to determine if these compounds have genotoxic activity. The results indicate that casiopeinas produce DNA fragmentation and base oxidation and suggest that their mode of action is related to reactive oxygen species (ROS) generation after copper reduction.
Subject(s)
Antineoplastic Agents/toxicity , Copper/toxicity , DNA Fragmentation/drug effects , Lymphocytes/drug effects , Organometallic Compounds/toxicity , Animals , Antineoplastic Agents/chemistry , Comet Assay , Copper/chemistry , DNA Repair , HeLa Cells , Humans , Mice , Models, Molecular , Molecular Structure , Mutagenicity Tests , Organometallic Compounds/chemistry , Oxidation-Reduction , Plasmids , Structure-Activity RelationshipABSTRACT
Transitional metals have a large variety of coordination numbers and geometries, accessible redox states in physiological conditions and a wide range of thermodynamic and reactivity properties which can be successfully tuned by selection of suitable ligands. These characteristics can be used to develop new drugs with numerous advantages over the organic based drugs. Historically, research in this field has focus on platinum and DNA targeting; however, anticancer drug research may be expanded to include alternative metal compounds with different mode of action resulting in markedly different cytotoxic response profiles. Cooper complexes with selected ligands are being extensively studied as agents for the treatment of cancer. Current research on copper compounds as antitumoral compounds is being reviewed in this chapter particularly focused on the family of copper Casiopeinas.
