published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Indole-3-carbinol (I3C) inhibits chemically induced tumor formation in rodents and rainbow trout. This study examines the effect of I3C and its analog, indole-3-acetonitrile (I3N) on xenobiotic-metabolizing enzyme systems. The modulation of these enzyme systems have been shown to have significant effects on the interaction of chemical carcinogens and cellular constituents. Rainbow trout were fed 500, 1000 and 2000 ppm dietary levels of I3C and 50, 500 and 1000 ppm dietary levels of I3N for 8 days. β-napthoflavone (BNF), which is also an effective anticarcinogen in the trout, was fed at a 500 ppm dietary level and was used as a positive LM4b (a cytochrome P-450 isozyme) inducing control. Enzyme activities assayed were: ethoxyresorufin-O-deethylase (EROD), ethoxycoumarin-O-deethylase (ECOD), glutathione S-transferase (GST), and uridine diphosphoglucuronosyl transferase (UDPGT). Total cytochrome P-450 content was determined spectrophotometrically by the CO reduced method. The specific P-450 isozymes, LM2 and LM4b, were detected quantitatively using the western blot method. The BNF diet induced EROD and ECOD activities by an average of 17 fold and 5.5 fold, respectively. Total P-450 content was increased 2-fold; the P-450 isozyme LM4b was induced more than 5-fold, but LM2 content remained unchanged. This diet increased UDPGT activity 1.5-2-fold, but GST activity was not induced by dietary BNF. Neither I3C nor I3N induced the activity levels of the enzymes assayed at any administered dietary levels, which have previously shown to inhibit tumor formation and reduce formation of carcinogen-DNA adducts. Thus, the anticarcinogenic mechanism of I3C may proceed in trout by mechanisms other than enzyme induction. Further experiments on the effect of I3C and I3C acid condensation products (RXN) on in vitro AFB1-DNA binding resulted in a 40% and 48% inhibition of AFB1-DNA binding by I3C and RXN, respectively. Additions of RXN at levels much lower than those estimated to exist in vivo in hepatic tissue resulted in a significant reduction in AFB1-DNA formation suggesting that even small levels of RXN offers protection against the genotoxic effect of AFB1. However, in vitro additions of neither I3C nor RXN had an effect on DNA binding using AFBI-CI₂, an aflatoxin analog that does not require enzymatic activation. These results suggest that the primary mechanism for I3C inhibition of AFB1 induced carcinogenesis may proceed by inhibiton of formation of the ultimate electrophile, i.e. by reversible inhibition of cytochrome P-450. / Graduation date: 1989

The use of metallo-pharmaceuticals, such as the platinum drugs, for cancer treatment illustrates the utility of metal complexes as therapeutic agents. Platinum group metal complexes therefore offer potential as anti-tumour agents to fight cancer. This study was aimed at synthesizing and evaluating the effects of palladium(II) and platinum(II) complexes as anticancer agents.

Extracts of the African potato have long been believed to have anti-cancer properties. The aim of the current research was to isolate hypoxoside (HYP) from Hypoxis hemerocallidea (African potato) and synthesize the dimethyl (DMH) and decaacetyl (DAH) derivatives and to test their selective cytotoxicity on a model consisting of a normal (MCF10A) and premalignant, invasive breast epithelial cells (MCF10A-NeoT). Hypoxoside was extracted from the H. hemerocallidea corms using ethanol, purified using a C-18 reverse phase column and the compound examined by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry and found to be of high purity. This was also the case for the synthesized compounds. To assess possible selective effects (cytotoxicity) of derivatized and underivatized hypoxoside, effects on the metabolism of premalignant and normal cells were assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Effects on cell number (total counts) and cell death [trypan blue and propidium iodide (PI) staining for dead cells versus a lack of staining for live cells] were, thereafter, assessed. Imaging of live adherent cells was also carried out using acridine orange (AO) and PI for live and dead cells (respectively). Propidium iodide staining of detached cells was carried out for flow cytometric determination of cell death (PI indicating early apoptotic or late apoptotic/necrotic cells). After treatment of normal (MCF10A) breast epithelial cells and premalignant cHa-rastransfected (MCF10A-NeoT) derivative breast epithelial cells with HYP, DMH and the DAH derivative, the MTS assay and the Duncan‟s multiple range, analysis of variance (ANOVA) post hoc analysis of the MTS results revealed that only the 150 and 300 µM DAH derivative had a statistically significant effect on the metabolic activity of the abnormal cell line relative to the dimethyl sulfoxide (DMSO) and revealed no significant effect on the normal MCF- 10A cell line after treatment with any of the test compounds. Supravital PI staining of adherent cells seemed to indicate a far higher rate of induction of cell death in abnormal cells than evident in the MTS assay and the PI-based flow cytometry or the trypan blue exclusion assays and need re-investigating, though result trends were similar. Total cell counts, show that HYP and its derivatives appear to increase both cancer and normal cell proliferation significantly, except in the case of DAH at 150 and 300 μM in the MCF10A-NeoT, without affecting the MCF-10A cell line. The trypan blue method for detection of cell death, together with total cell counts, the Duncan‟s analysis of MTS results and a 24 hour exposure to test compounds, seems to constitute an optimal system for drug screening and indicates the statistically significant selective toxicity of the DAH compound at 150 and 300 μM in the MCF10A-NeoT, suggesting that the DAH derivative at 150 and 300 µM would have significant, selective therapeutic potential on Ras-related malignancies. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2013.

Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / Department of Chemistry

In recent years more and more researchers have begun to use data mining and machine learning tools to analyze gene microarray data. In this thesis we have collected a selection of datasets revolving around prediction of patient response in the specific area of breast cancer treatment. The datasets collected in this paper are all obtained from gene chips, which have become the industry standard in measurement of gene expression. In this thesis we will discuss the methods and procedures used in the studies to analyze the datasets and their effects on treatment prediction with a particular interest in the selection of genes for predicting patient response. We will also analyze the datasets on our own in a uniform manner to determine the validity of these datasets in terms of learning potential and provide strategies for future work which explore how to best identify gene signatures. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2014. / FAU Electronic Theses and Dissertations Collection

Nos últimos anos as evidências de novos casos de câncer têm alarmado o mundo. O objetivo desse trabalho foi avaliar possíveis propriedades antineoplásicas atribuídas ao óleo de Copaifera reticulata Ducke pela etnofarmacologia. Ocorreu pela análise da citotoxicidade deste em cultivos de células normais e cancerosas de pulmão, murinas E10 e E9 e humanas das linhagens NCI-H460 e NCI-H2023. Os cultivos após serem incubados a 37°C foram expostos a oito diferentes concentrações do óleo diluído em meio de cultivo permanecendo em estufa por 48 h na mesma temperatura. Decorrido esse tempo, adicionou-se o reagente MTT para leitura espectrofotométrica. Com a avaliação dos resultados dessa leitura, observou-se um grande potencial antitumoral do referido óleo, determinando-se sua IC50 para todas as células estudadas. Através da observação e captação de imagens microscópicas foi possível observar alterações morfológicas nas células nas diferentes concentrações do tratamento, havendo diferença entre a quantidade de células viáveis normais e neoplásicas. Concluiu-se que o óleo de Copaifera reticulata Ducke demonstrou efeito antineoplásico em duas linhagens de células neoplásicas do pulmão humano, bem como na linhagem murina E9, sendo que estudos efetuados para a caracterização de apoptose por fluorescência e alterações no ciclo celular nas células humanas reiteraram seu potencial como um agente contra o câncer. / In recent years evidences of new cancer cases in the world have been alarmed. The aim of this study was to evaluate the antineoplastic properties attributed to the Cofaífera retículata Ducke oil by ethnopharmacology. These analysis of cytotoxicity occurred through this normal murine cells E10 and lung cancer murine cells E9 and human lung cancer cell lines NCI-H460 and NCI-H2023. The cultures after being incubated at 37°C were exposed with eight different oil concentrations diluted in warmed culture medium, remaining in incubator for 48 hours at the same temperature. After this time, added MTT reagent for spectrophotometric reading. With this reading analysis results it was observed a great potential antitumor of this oil determining their IC50 for ali cells studied. Through the microscopic images were possible to observe morphological changes in cells in different concentration of the oil exposure, differentiating normal cells from neoplastic cells. It was concluded that the Cofaífera retículata Ducke oil has the antineoplastic effect in two human lung cancer cell lines of as well as in murine cells E9, but the effect was not observed in E10 under the same conditions. Studies made in order to apoptosis characterization by fluorescence and cell cycle changes in human cells, confirming its potential as agent against cancer.

Cancer is the second leading cause of death in the western world. In order to treat various types of cancer, platinum-based drugs are most widely employed as metal-containing chemotherapeutic agents. However, their clinical usage is hindered by toxic side effects, and by the emergence of drug resistance. Our focus was to replace platinum with less toxic metal like tin which can give better alternatives for cancer treatment. The major aim of our study was to synthesize novel organotin polyethers (Sn-O) which can be used to combat cancer. Preliminary results from our laboratory using organotin polyethers, that were synthesized by varying the structure of diols showed growth inhibition in Balb-3T3 cells. This study directly led us to hypothesize the two structural windows, first by changing the distance between diol and second, by presence of unsaturation in diols, the biological activity of organotin polyethers (Sn-O) can be enhanced significantly. Different series of polymeric compounds were synthesized based upon these two structural windows and the formation of products was validated using standard techniques like infrared spectroscopy (IR), light scattering photometer, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and nuclear magnetic resonance (NMR). The synthesized polymers arrested the growth of cancer cell lines including bone, prostate, colon, breast, pancreas and lung cancer derived cell lines in vitro. In number of instances where chemotherapeutic index values of two and greater were found that these polymers are significantly more active against cancer cells than non-cancerous cells in culture. / These results support the starting premise that the polymers may exhibit cancer cell selectivity. In general, it was found that the presence of unsaturation increased the probability that the polyether would inhibit the growth of various cancer cell lines. Further, in some cases, polyethers with short distances between the oxygen atoms showed a superior ability to inhibit the growth of various cancer cell lines in comparison to those with longer distances between the oxygen atoms. These results provide a framework for the discovery of novel cancer therapeutics. / by Girish Vallabhbhai Barot. / Thesis (Ph.D.)--Florida Atlantic University, 2009. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2009. Mode of access: World Wide Web.