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Pellacani, Claudia (2008) Citotossicità e genotossicità in linee cellulari umane di nuovi composti anti-protozoari e anti-cancerogeni. [Tesi di dottorato]

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Abstract (inglese)

Different innovative methods, in parallel with the traditional tests of toxicology, have been applied on the determination of the DNA damage, in an attempt to reveal genotoxic effects evoked by drugs. Given the close relationship between mutagenic and cancerogenic activity, it is indeed necessary to estimate the ability of compounds developed for therapeutic application in modifying the structure and/or function of DNA. The aim of the mutagenesis tests is then to disclose the potential genotoxic effects of medicaments and to characterize the possible mechanisms that are responsible of cancerogenesis. In addition, such tests allow to estimate of the risk to which the population could be exposed, when treated with these novel compounds.
The first part of this study consists on the valuation of the potential toxicity of novel chemioterapics, namely two tiosemicarbazonic complexes of Copper and Nickel. These compounds have been tested and compared in human leukocytes and in p-53 mutated cells (U937) by the Comet assay (1h-treatment).
Cytometrical flow tests showed the ability of these complexes to induce apoptosis on U937. Moreover the Ni-based complex is able to activate the caspase-3 and to perturb cell cycle progression, showing an increase in G2/M phase fraction and a decrease of G0/G1 cells.

In this study, we also estimated possible cito- and geno-toxics effects induced by two different series of antiparassite agents. These compounds could have future application in the treatment of trypanosomiasis, which, according to statistical data from the World Health Organization, represents the main cause of human death. The currently-used drugs for the treatment of such disease are weak and not suitable for chronic therapies, due to the occurrence of toxic effects and pharmacoresistence. Therefore, it is mandatory to discover new highly effective drugs, devoid of noxious effects.
The estimate of the cytotoxic and genotoxic effects of these compounds has been carried out in vitro, using bacterial and human cells (Revers bacterial test in Salmonella typhimurium, Micronuclei assay, Comet Assay). These tests are suitable to investigate the possible cyto- and genotoxic effects on the host cells, as well as the mechanisms involved on the interaction between drugs and exposed cells.
The first group of new drugs was composed by three different compounds for the therapy of American trypanosomiasis (5-nitromegazol and two of its analogues, 4-nitromegazol and 1-methyl-5-nitro-2-imidazolecarboxaldehyde 5-nitroimidazole thiosemicarbazone). These molecules were tested by the Comet assay, performed at different pH levels, to better identify the nature of DNA damage. The oxidative damage to DNA was also measured by using the Comet assay, using a modified protocol including endonucleases.
DNA damage was found in 5-nitromegazol-, but not in 4-nitromegazol-treated cells. Oxidative stress was the main causative factor of DNA damage by 5-nitromegazol, as suggested by the reparative effect of endonucleases. In turn, 5-nitroimidazole-thiosemicarbazone induced DNA damage with a higher efficiency than 5-nitromegazol.
The second group of new compounds was composed by some novel nitroheterocycles bound with triazine, created as future remedies of African trypanosomiasis. Results obtained have shown that the different substitutions to the melamine ring, which characterises the chemical structure of these compounds, are associated to a different degree of genotoxic effects in host cells.
Data provide useful indications for future structure-activity studies (analysis QSAR) and to plan new experiments in animal models, where the (chemio)terapeutic effect of these compounds may be evaluated.

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Tipo di EPrint:Tesi di dottorato
Relatore:Poli, Enzo
Dottorato (corsi e scuole):Ciclo 20 > Corsi per il 20simo ciclo > FARMACOLOGIA E TOSSICOLOGIA, TERAPIA RIANIMATIVA E INTENSIVA
Data di deposito della tesi:31 Gennaio 2008
Anno di Pubblicazione:31 Gennaio 2008
Parole chiave (italiano / inglese):tripanosomiasi, cancro, tiosemicarbazoni, genotossicità, citotossicità, danno al DNA
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Area 05 - Scienze biologiche > BIO/18 Genetica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Farmacologia ed Anestesiologia "E. Meneghetti"
Codice ID:269
Depositato il:10 Nov 2008
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