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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Synthesis of 10, 11, 12, 12a, 12b, 13-hexahydro-5hbenzo[f]cyclopropa[d]pyrido[1,2-b] isoquinoline-5,7(9H)dione and related compounds

Tinkleman, Joseph M. Smith, Forrest T., January 2009 (has links)
Thesis (Ph. D.)--Auburn University. / Abstract. Vita. Includes bibliographical references (p. 134-137).

Molecular mechanism for DNA recognition by DNA alkylating antitumor agents /

Lee, Seung-joo, January 1999 (has links)
Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 138-144). Available also in a digital version from Dissertation Abstracts.

Comparative studies of alkylating and N-heterocyclic compounds on different genetic endpoints with special emphasis on amplification of minisatellite sequences

Agurell, Eva. January 1992 (has links)
Thesis (doctoral)--Stockholm University, 1992. / Includes bibliographical references.

Effects of cyclophosphamide on ulcer in rat stomachs /

Lo, Kwun-hang, Kenny. January 2004 (has links)
Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Model studies relating to the mode of action of O'6-alkylguanine-DNA alkyltransferase

Frith, Richard William January 1993 (has links)
No description available.


Dierickx, Karen 05 November 2008 (has links)
The search for more effective treatment strategies in melanoma led to many new innovative approaches aiming at different molecular targets. Chemotherapy still remains the most effective treatment and many efforts are put in order to improve targeting and delivery of the chemotherapeutic agents. Among these, peptide conjugates of anticancer drugs were designed to increase stability, cell penetration, specificity and accumulation in cancer cells. We as well as others evaluated such a conjugate, termed PSF (L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine-ethylester) in terms of its cytotoxicity in vitro and in vivo using a human melanoma tumor as a model, its stability, transport, and metabolisation. By comparing the cytotoxicity of PSF and melphalan towards different cancer primary melanoma cell cultures, we noticed some interesting observations: PSF displayed the same toxicity pattern both in short (2h) and long term (24h) cell exposures whereas melphalan and m-sarcolysin needed long term exposure to reach the same toxicity. This could indicate that PSF very quickly penetrates the cells in accordance with what has been shown with red blood cells (RBCs). PSF has shown a much better and quicker penetration into the cells in vitro as compared to melphalan. In this present work, the cytotoxic effect of PSF was further evaluated in vivo using a standardized nude mice tumor model bearing a human melanoma. First, the acute toxicity in rats and mice and the maximum tolerated dose were determined. After a dose-escalation study one dose was singled out and tested as a single dose and as a fractionated dose. PSF was able to reach the tumor site and a dose-response relationship was observed. The IP administration of fractionated doses of PSF had significantly better effect on tumor growth inhibition, regression and regrowth than single dose administration and this without any evidence for general toxicity monitored by animal weight loss. We also compared the efficacy of PSF to its parent drug m-sarcolysin, melphalan and cyclophosphamide and observed that PSF was much more active than both melphalan and m-sarcolysin at the same molar doses. Body distribution of the 14C-labelled PSF revealed ratios of 2.4 and 1.5 compared to muscle tissue for the two melanoma tumors evaluated with no significant and stable accumulation in any vital organ. The amount of tracer was still high in the blood after 24 hours explaining the high radioactivity in the kidney and partly in the liver. Interestingly, the spleen had an unusual high radioactivity uptake reflecting the exceptional binding of the tracer to blood cells (BC), while the pancreas very high load was an indicator of protease-mediated specific delivery and strongly support our hypothesis elaborated on the basis of in vitro results. Our in vitro data point to a particular mechanism of action of PSF based on the transport of PSF through the body by the rapid binding to blood cells and the delivery at the tumor site by the subsequent release of its active metabolites due to cleavage by tumor-associated proteases. Concerning the binding of PSF to membranes and its transport the following observations were made: while PSF was stable in human plasma, it disappeared very quickly in whole blood along with the generation of a main metabolite: m-sarcolysin. The presence of BC membranes was required for both binding and generating the metabolites. Binding to natural or artificial membranes was achieved and only competition with melanoma cells or proteolytic enzymes such as dispase, led to the generation of active metabolites. The different metabolites were isolated using preparative LC and were then identified using Electrospray Ionisation Mass Spectrometry (ESI). Three metabolites, of which m-sarcolysin was the main one, were identified all bearing the chloroethyl alkylating group. Enzymatic catalysis was further supported by a set of experiments where the enzymatic activity was non-specifically and specifically inhibited. In order to look at the effect of extracellular matrix proteases on PSF, three representatives of ECM proteases were incubated with PSF: collagenase A had no effect, but both dispase and trypsine were able to process PSF. The following data indicate the higher processing of PSF in the presence of cells with a higher proteolytic activity and thus the delivery of the blood cell-bound PSF. When comparing BC with melanoma cells (MC), the latter showed a higher ability to bind and process PSF both by membrane-associated and most interestingly soluble proteases. A lot of families of enzymes are reported to be overexpressed by melanoma cells including: metalloproteases, cysteine cathepsins, serine proteases and aminopeptidases. All the melanoma cells and cell lines evaluated were able to generate PSF active metabolites. To identify the families of enzymes expressed on the membrane of melanoma cells that might be involved in the mechanism of action of PSF, we performed 2D-gel electrophoresis on their membrane extracts. The 2D-gels experiments revealed the presence of proteins compatible with enzymes known to be important in melanoma and further work is needed to identify the individual enzymes involved by using mass spectrometry and Western blotting. Both our in vitro and in vivo findings strongly suggest that not only melanoma tumor cells and tumor sites but other types of tumors as well may be targets for the toxic activity of PSF owing to their much higher load in proteolytic enzymes that are closely related to their invasive potential. The transport of PSF by the blood cells and the release of its metabolites at the tumor site result in a low amount of drug in its free soluble form within the blood and this may explain the relatively lower side-effects observed. PSF is thus expected to have a much better therapeutic index than conventional alkylating agents. This original mechanism of drug delivery may well be extended to other cancer and non-cancer drugs than alkylating agents.

The role of granulocyte-macrophage colony-stimulating factor and alpha-tumor necrosis factor in accelerated recovery from cyclophosphamide-induced leukopenia in mice administered a traditional Chinese medicine, Bu-zhong-qi-tang /

Sinn, Wai-hang. January 2005 (has links)
Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Development, characterisation and application of an immunofluorescence method for the quantification of melphalan-DNA adducts in individual cells

Frank, Adrian John January 1998 (has links)
No description available.

Effects of cyclophosphamide on ulcer in rat stomachs

盧冠恆, Lo, Kwun-hang, Kenny. January 2004 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

The role of granulocyte-macrophage colony-stimulating factor andalpha-tumor necrosis factor in accelerated recovery fromcyclophosphamide-induced leukopenia in mice administered a traditionalChinese medicine, Bu-zhong-qi-tang

Sinn, Wai-hang., 冼惠恆. January 2005 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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