published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

Modifications of cellular responses to epidermal growth factor (EGF) induced by tumor promoters and anti-promoters were examined. The effect of the promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) EGF binding was studied using mouse epidermal cells. Initially, TPA decreased EGF binding. However, when cells were incubated continuously in TPA plus a low concentration of EGF, more EGF bound to TPA-treated cells than to control cells. It was shown that the effects of TPA were partially reversible and that the greater amount of EGF bound to TPA-treated cells over controls after long-term incubation was due to larger amounts of whole EGF in the media of TPA-treated cells when cells have regained their ability to bind EGF. The ability of TPA to induce DNA synthesis synergistically with EGF may depend on the transient sparing of EGF from degradation and subsequent binding of the spared EGF. Fluocinolone acetonide (FA) and retinoic acid (RA) are potent anti-promoters able to induce increased EGF binding. The possibility that these compounds exerted their anti-promoting activities through offsetting TPA-induced EGF binding alterations was studied. Rat-1 fibroblasts were used to examine the effect of FA on TPA-mediated changes in EGF binding and EGF-induced ornithine decarboxylase (ODC) activity and DNA synthesis. Pretreatment with FA caused increased EGF binding and decreased ODC activity and DNA synthesis stimulated by high or low EGF concentrations. The glucocorticoid lowered ODC and DNA synthesis induced by EGF in combination with TPA to levels closer to control (EGF alone) levels. These data indicated that the anti-hyperplasiagenic effect of FA may be partially mediated through the EGF receptor. The effects of RA on EGF binding and EGF-induced cellular responses were examined in Rat-1 and Swiss 3T3 fibroblasts. Pretreatment with RA resulted in increased EGF binding to 3T3 cells only. However, RA treatment was able to enhance ODC activity in both cell lines. Retinoic acid binding protein was detected only in Rat-1 cells. It was therefore unlikely that the effects of RA on ODC induction were mediated by either altered EGF binding or the presence of CRABP. Experiments with 3T3 cells demonstrated that TPA alone was able to induce ODC activity. It is therefore possible that TPA exerts part of its tumor promoting action through the EGF receptor, but other sites of action also contribute to its promoting properties.

Two new synthetic methods for the construction of the C-D moiety of streptonigrin have been developed. The first is the cyclization of beta, gamma unsaturated ketals to cyanopyridines. These ketals were prepared from akylidenemalononitriles. The second method utilized is the ortho-directed metalation of benzamide or oxazoline derivative to give keto compounds. However, attempts to transform these keto compounds to akylidenemalononitriles by Knoevenagel condensations were unsuccessful. With the ease of the reaction and ready availability of starting materials, the beta, gamma unsaturated ketals offer versatile synthons for pyridine C ring synthesis.

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