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Amifostine (WR-2721, Ethyol®), a phosphorylated thiol, demonstrates the unique ability to protect normal but not tumour tissue from cytotoxic damage induced by radiation therapy and chemotherapy. This study tested the effect of amifostine's active metabolite, the free thiol, WR-1065, on the cytotoxicity of standard anticancer drugs against human A2780 ovarian and MCF7 breast cancer cell lines in vitro, using the well-characterised sulphorhodamine B assay. 50% inhibitory concentration (IC50) values were determined for each of 16 different anticancer drugs in the presence and absence of the highest nontoxic dose of WR-1065 from concentration-response curves constructed in triplicate and based on 18 replicate cell culture plates for each tested drug concentration. Pretreatment with WR-1065 had no statistically significant effect on the IC50 value of any of the 16 drugs tested against either the A2780 or MCF7 human tumour cells. These data expand upon previous reports showing that amifostine does not protect tumours from the cytotoxic effects of anticancer agents. The ability of amifostine to protect against dose-limiting toxicity to a variety of normal tissues without protection of tumour should enhance the efficacy ratio of a wide range of standard anticancer drugs.

Cryopreservation is a promising approach to long-term biopreservation of living cells, tissues and organs. The use of cryoprotective agents (CPAs) in combination with extremely low temperatures is mandatory for optimum biopreservation. CPAs (e.g., glycerol, trehalose, dimethyl sulphoxide (DMSO)), however, are relatively cytotoxic and compromise biopreserved cell quality. This is usually resultant in oxidative damage, diminishing cell functionality and survival rate. The growing market of cell therapy medicinal products (CTMPs) demands effective cryopreservation with greater safety, of which the currently available CPAs are unable to provide. The present study was aimed at developing cryomedia formulation to enhance the cryopreservation of nucleated and anucleated mammalian cells. Here, eleven compounds of a polyol nature were selected and examined for their cryoprotective properties. These compounds are derived from plants and honey, thereby ensuring their safety for human consumption. The selection was based on their molecular structure and chemical properties. Here, the presented study is divided into three main phases: 1) Screening the compounds panel for cryo-additive effects on cells during and post-cryopreservation and optimising the dose response and time course for trehalose and glycerol with and without the novel compounds; 2) Assessing the influence of biophysical criteria on biospecimen cryopreservation (e.g., biosampling procedure, cell age, donor age); 3) Establishing the mechanisms of action underpinning the modulatory effect of novel CPAs on biological pathways during cryopreservation. For the stated purposes, red blood cells (RBCs) obtained from sheep and humans were used to screen the compounds for novel cryo-additive agents. Cryosurvival rate was employed as an indication of the compounds' cryoprotective performance. Cellular biochemical profiles, including lipid and protein oxidative damage as well as key redox enzymatic activities (e.g., lactate dehydrogenase (LDH), glutathione reductase (GR)) were measured. The study revealed that nigerose (Nig) and salidroside (Sal) were significantly effective in protecting cells during the freeze-thaw cycle and recovery phases. Both compounds promoted the activity of GR and reduced oxidative stress mirrored by diminished LDH activity. This was also reflected in the protein and lipid oxidation levels, which was limited to a comparable level with the cells' prior freezing. Further studies on human leukaemia (HL-60) were carried out to elucidate the molecular and biological pathways associated with cryodamage and the modulatory effects of adding novel CPAs. The proteome profile and the corresponding biological functions were evaluated and iii showed that Nig and Sal protected cells against cryodamage. The additive compounds (Nig and Sal) demonstrated a unique and overlapping modulation effect pattern. Nig was found to highly influence proteins engaged with metabolic and energetic pathways, whereas Sal greatly affected nuclear and DNA-binding proteins. The current study concluded that novel CPAs have high potency in protecting cells and each compound has a unique effect on the cellular proteome. These features can be applied to designing cryomedia formulae with higher protective efficiency for targeted applications in cell based therapy and biopharmaceutical industries.

Many experiments are being conducted to find compounds that offer radioprotection against radiation damage and that are also non-toxic. It is hopeful that in the future, research for this technology will benefit patients undergoing cancer treatment by reducing radiation damage to normal cells and therefore reducing short and long term side effects experienced from treatments. Hamster cells were irradiated at doses of 60 and 120 rad, with and without Sphingosine-1-Phosphate mixed in with their growth medium. Post irradiation, it was observed that the S1P molecule seemed to have a radioprotective effect by decreasing the amount of cell death compared to the amount of cell death that occurred with the absence of the molecule. The results of this experiment will sent to Dr. Jon Tilly at Massachusetts General Hospital. Dr. Tilly is currently researching S1P as a possible radioprotector. / Graduation date: 2003

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.

Resumo: O objetivo deste estudo foi avaliar a influência da fotopolimerização gradual no deslocamento de materiais protetores pulpares em função da contração de polimerização da resina composta através da formação de microfendas nas interfaces: estrutura dental/material protetor pulpar/ resina composta. Cavidades classe V, com dimensões padronizadas foram preparadas nas faces V e L de 20 terceiros molares humanos, divididos em 4 grupos de acordo com o material protetor pulpar e técnica de fotopolimerização: (1) Ketac Molar Easymix, 3M ESPE - (IVQ) + Fotopolimerização convencional - 850mW/cmø por 20s (FC); (2) IVQ + Fotopolimerização gradual - 100 mW/cm2 até 1000 mW/cm2 por 10s e 1000 mW/cm2 por 10s (FG); (3) Vitrebond 3M ESPE (IVR) + FC; (4) IVR +FG. Todas as cavidades foram restauradas com sistema adesivo Single Bond (3M ESPE) e resina composta híbrida Four Seasons (Ivoclar Vivadent). O aparelho fotopolimerizador utizado foi Optilux 501 (Demetron - Kerr) no modo convenciona e gradual (RAMP). Após ciclagem térmica um segmento longitudinal de 2 mm de espessura foi obtido na porção central de cada restauração e, em seguida, submetidos às etapas de fixação e desidratação em grau ascendente de etanol. A adaptação interna dos materiais à parede axial foi analisada em MEV, com 1000x de magnificação. A análise estatística realizada pela ANOVA a dois critérios de avaliação e pelos testes de Levene e Shapiro-Wilk (p_0,05) mostrou haver significância estatística entre as técnicas de fotopolimerização convencional e gradual (Ramp). Há evidência de que a fotopolimerização convencional produz, em 13 média, fendas maiores do que a fotopolimerização gradual. / Abstract: The aim of this study was to evaluate the influence of gradual photolymerization on the displacement of pulp protective materials due to the resinþs photopolymerization contraction trough the formation of gaps on the following interfaces: dental structure/ pulp protective material/ composite resin. Class V cavities with standardized dimensions were prepared on the buccal and lingual surfaces of 20 human sound third molars, divided into 4 groups according to their pulp protective material and photopolymerization technique:(1) Ketac Molar Easymix, 3M ESPE- (IVQ) + Conventional photopolymerization-850 mW/cm2 for 20 seconds (FC); (2) IVQ + gradual photopolymerization-100 mW/cm2 to 1000 mW/CM2 for 10 seconds and 1000 Mw/CM2 for 10 seconds (FG); (3) Vitrebond 3M ESPE (IVR)+ FC; (4) IVR + FG.All cavities were restored using the adhesive system Single Bond (3M ESPE) and hybrid composite resin Four Seasons (Ivoclar Vivadent). The device used for photopolymerization was the Optilux 501 (Demetron-Kerr) in both conventional and gradual (RAMP) modes. After thermal cycling, a longitudinal segment of 2 mm of thickness was obtained from the central part of every restoration, and submitted to fixation and dehydration with uprising levels of ethanol processes. The internal adaptation of the materials to the axial wall of the preparation was analyzed in 16 SEM with 1,000x of magnification. The statistical analysis was made using two-way ANOVA and Levene and Shapiro-Wilk (p _ 0,05) tests. Results showed statistically significant differences between the gradual (RAMP) and conventional photopolymerization techniques. There are evidences that the conventional technique creates wider gaps than the gradual technique. / Orientador: Alexandre Henrique Susin / Coorientador: Osmir Batista de Oliveira Junior / Banca: Marcelo Ferrarezi de Andrade / Banca: Roselaine Terezinha Pozzobon / Doutor

Made available in DSpace on 2014-06-11T19:31:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-01Bitstream added on 2014-06-13T21:02:28Z : No. of bitstreams: 1 souza_nc_me_arafo.pdf: 1115015 bytes, checksum: 8487455e45f6d12782f7b081be948890 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo deste estudo foi avaliar a influência da fotopolimerização gradual no deslocamento de materiais protetores pulpares em função da contração de polimerização da resina composta através da formação de microfendas nas interfaces: estrutura dental/material protetor pulpar/ resina composta. Cavidades classe V, com dimensões padronizadas foram preparadas nas faces V e L de 20 terceiros molares humanos, divididos em 4 grupos de acordo com o material protetor pulpar e técnica de fotopolimerização: (1) Ketac Molar Easymix, 3M ESPE - (IVQ) + Fotopolimerização convencional - 850mW/cmø por 20s (FC); (2) IVQ + Fotopolimerização gradual - 100 mW/cm2 até 1000 mW/cm2 por 10s e 1000 mW/cm2 por 10s (FG); (3) Vitrebond 3M ESPE (IVR) + FC; (4) IVR +FG. Todas as cavidades foram restauradas com sistema adesivo Single Bond (3M ESPE) e resina composta híbrida Four Seasons (Ivoclar Vivadent). O aparelho fotopolimerizador utizado foi Optilux 501 (Demetron - Kerr) no modo convenciona e gradual (RAMP). Após ciclagem térmica um segmento longitudinal de 2 mm de espessura foi obtido na porção central de cada restauração e, em seguida, submetidos às etapas de fixação e desidratação em grau ascendente de etanol. A adaptação interna dos materiais à parede axial foi analisada em MEV, com 1000x de magnificação. A análise estatística realizada pela ANOVA a dois critérios de avaliação e pelos testes de Levene e Shapiro-Wilk (p_0,05) mostrou haver significância estatística entre as técnicas de fotopolimerização convencional e gradual (Ramp). Há evidência de que a fotopolimerização convencional produz, em 13 média, fendas maiores do que a fotopolimerização gradual. / The aim of this study was to evaluate the influence of gradual photolymerization on the displacement of pulp protective materials due to the resinþs photopolymerization contraction trough the formation of gaps on the following interfaces: dental structure/ pulp protective material/ composite resin. Class V cavities with standardized dimensions were prepared on the buccal and lingual surfaces of 20 human sound third molars, divided into 4 groups according to their pulp protective material and photopolymerization technique:(1) Ketac Molar Easymix, 3M ESPE- (IVQ) + Conventional photopolymerization-850 mW/cm2 for 20 seconds (FC); (2) IVQ + gradual photopolymerization-100 mW/cm2 to 1000 mW/CM2 for 10 seconds and 1000 Mw/CM2 for 10 seconds (FG); (3) Vitrebond 3M ESPE (IVR)+ FC; (4) IVR + FG.All cavities were restored using the adhesive system Single Bond (3M ESPE) and hybrid composite resin Four Seasons (Ivoclar Vivadent). The device used for photopolymerization was the Optilux 501 (Demetron-Kerr) in both conventional and gradual (RAMP) modes. After thermal cycling, a longitudinal segment of 2 mm of thickness was obtained from the central part of every restoration, and submitted to fixation and dehydration with uprising levels of ethanol processes. The internal adaptation of the materials to the axial wall of the preparation was analyzed in 16 SEM with 1,000x of magnification. The statistical analysis was made using two-way ANOVA and Levene and Shapiro-Wilk (p _ 0,05) tests. Results showed statistically significant differences between the gradual (RAMP) and conventional photopolymerization techniques. There are evidences that the conventional technique creates wider gaps than the gradual technique.