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Total synthesis of 6-methoxylavendamycin analogsErasga, Noe O. January 1999 (has links)
The synthesis of 6-methoxylavendamycin methyl ester (39) and 6-methoxy detnethyllavendamycin methyl ester (40) is reported. Also the synthesis of 7-propionamido-2-methylquinoline-5,8-dione (33) and 7propionamido-3-methylquinoline-5,8-dione (34) via the Diels-Alder reaction is described.The Pictet-Spengler condensation of 7-amino-6-methoxy-2-formylquinoline-5,8-dione (37) with 8-methyltryptophan methyl ester (4) and tryptophan methyl ester (38), produced respectively the lavendamycin analogs 39 and 40.Aldehyde 37 was prepared by the oxidation of 7-amino-6-methoxy-2methylauinoline-5,8-dione (47) with selenium dioxide under reflux in dry 1,4-dioxane.Our original plan for the synthesis of aldehyde 37 via 7-bromo-6methoxy-2-methylquinoline-5,8-dione (36) was not successful. The DielsAlder reaction of 3-methoxy-2,6-dibromobenzoquinone (35) and N-(O-(t-butyldimethylsilyloxy)]-2-methyl-1-aza-1,3-butadiene (11) gave a very low yield of 36 and consequently this route was abandoned.An alternate known multistep route was chosen to produce the bromoquinolinedione 36. Reaction of 4-methoxy-2-nitroaniline (41) with crotonaldehyde (42) gave 6-methoxy-2-methyl-8-nitroquinoline-5,8-dione (43). Subsequent nitration, reduction, oxidation, and bromination of mononitroquinoline 43 yielded the desired bromoquinolinedione 36 with success. A change to Boger's procedure in the next reaction involving the azido intermediate 46 was done due to its effectiveness in producing a greater yield and purer product than that of Liao's procedure. The final preparation of 7-amino-6-methoxy-2-methylquinoline-5,8-dione (47) was accomplished by the hydrogenation of azidoquinolinedione 46 in the presence of platinum oxide in anhydrous methanol.Two other quinolinediones, 33 and 34, were earlier synthesized using the Diels-Alder reaction. Quinolinediones 33 and 34 were prepared by reacting 2-propionamido-6-bromobenzoquinone (32) with azadienes 11 and 19 to respectively yield 7-propionamido-2-methylquinoline-5,8-dione (33) and 7propionamido-3-methylquinoline-5,8-dione (34).Bromobenzoquinone 32 was prepared according to Kelly's method of preparation. 2,4-Dibromophenol (48) was nitrated, reduced, propionylated, hydrolyzed, and finally oxidized to produce 2-propionamido-6bromobenzoquinone (32). / Department of Chemistry
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Quality of life differences among long-term cancer survivors based upon cancer type and number of treatment types / Quality of life differences among long-term survivors based upon cancer type and number of treatments typesChristy, Shannon M. 24 July 2010 (has links)
More than 10 million cancer survivors are now living in the United States. Using the QOL-CS, a measure of quality of life of cancer survivors, the current study considered quality of life differences in 115 cancer survivors based upon three cancer types (breast, prostate, and colon cancers) and number of types of cancer treatments received. It was hypothesized that differences in HRQOL would be found between the cancer type and number of treatment types received. Results were mixed. MANOVA analysis revealed statistically significant differences based upon cancer type. Breast cancer survivors had significantly higher scores than prostate cancer survivors on social well-being, and prostate cancer survivors demonstrated significantly higher scores on psychological well-being than breast cancer survivors. No differences in HRQOL were found between the two groups based upon the number of treatment types received. Limitations of the study are reviewed and implications for future research and counseling are considered. / Department of Counseling Psychology and Guidance Services
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Image analysis for patient management in colorectal cancerBond, Sarah Louise January 2006 (has links)
Secondly, we incorporate knowledge of the physiology, or how we expect the anatomy to change due to treatment. We can represent these changes using the Jacobian of the deformation, which describes the local size and type of change. This is used to regularise the registration, and can be incorporated simultaneously with the iterations of the registration. The final result is an accurate and robust registration result that is clinically useful for finding corresponding features on pre- and post-treatment datasets.
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Synovial sarcoma : translating gene expression into patient careTerry, Jefferson 05 1900 (has links)
Synovial sarcoma is a soft tissue tumor defined by the presence of t(X;18)(p11.2;q11.2), fusing the SYT (SS18) gene on chromosome 18 and one of three SSX genes on chromosome X. T(X;18) results in production of a fusion protein (SYT-SSX) that is thought to underlie synovial sarcoma pathogenesis through aberrant targeting of both activating (trithorax, SWI/SNF) and repressing (Polycomb) transcription factors when expressed in a stem or progenitor-like cellular background.
Clinically, synovial sarcomas present considerable diagnostic and therapeutic challenges. Whereas the classical biphasic histology is distinctive, the more common monophasic histology can be difficult to differentiate from other spindle cell tumors. In these situations, detection of t(X;18) is the gold standard for diagnosis, but it is a specialized and time-consuming process. Immunohistochemistry can be helpful, but no marker that is both highly sensitive and specific is available. Here I describe a fluorescence in situ hybridization based method employing an SYT break-apart probe set that can expedite detection of t(X;18). I also report that TLE1, which was identified in gene expression studies as a good discriminator of synovial sarcoma from other mesenchymal tumors, is a highly sensitive and specific immunohistochemical marker for synovial sarcoma. Both of these novel diagnostic techniques are applicable to small tissue samples such as core needle biopsies and are now being used clinically.
The diagnosis of synovial sarcoma carries a poor prognosis and the 10-year overall survival rate is approximately 50%, most of whom are young adults. The addition of chemotherapy to surgical resection (the mainstay of treatment) does not appear to improve overall survival. Thus, there is a strong need for development of a clinically effective systemic therapy to improve patient outcome. I describe preclinical studies that demonstrate the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits proliferation of synovial sarcoma by inducing apoptosis and that this is associated with degradation of multiple receptor tyrosine kinases and disruption of the SYT-SSX-β-catenin interaction. I also identify a subset of synovial sarcoma cells, typified by expression of CD133, which exhibit stem-like properties and are relatively resistant to doxorubicin but susceptible to 17-AAG at clinically relevant concentrations.
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Chemosensitivity of prostatic tumour cell lines under conditions of G2 block abrogationSerafin, Antonio Mendes January 2000 (has links)
Thesis (MTech (Biomedical Technology))--Cape Technikon, 2011. / Cancer of the prostate gland is now recognised as one of the principal medical problems in males.
In the USA, cancer of the prostate is the second most commonly diagnosed cancer after skin cancer
and the second most common cause of death from cancer after lung cancer. In South Africa,
prostate cancer is the second most common cancer, with an estimated annual incidence of 19.1 per
LOO000 men (Sitas, 1994). However, this incidence is probably under-estimated, due to incomplete
records. Comparison of the incidence of prostate cancer in the different racial groups shows that it
is the second most common malignancy in the White, Black (African) and Mixed (Coloured) race
groups, and the fourth most common malignancy in Asian (Indian) men in South Africa.
Metastatic prostate cancer is refractory to hormone therapy and remains incurable. Hence, novel
therapeutic approaches are needed. These anticancer drugs can be tested in tumour cell lines, and
cell culture methods also permit testing of optimum conditions.
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Synthesis and characterisation of ³²P labelled bisphosphonates conjugated carbon nanotubes as a potential chemo and radiotherapeutic system for the treatment of secondary bone cancerDlamini, Njabuliso Lucia 02 May 2012 (has links)
M.Sc. / The statistical proof that most forms of cancer metastasize to bone has redirected the focus of secondary bone cancer to probe into the most efficient forms of treatment. Due to the fact that secondary bone cancer delocalizes to bone, chemotherapy has been established as an efficient form of treatment. Bisphosphonates is one chemotherapeutic agent that has shown a great potency in treating bone related sicknesses. Bisphosphonates are analogues of pyrophosphates that are characterized by the presence of two P-C bonds. They have a very high affinity for bone undergoing renewal and are thus able to inhibit tumour induced resorption. Bisphosphonates’ efficiency is however reduced due to that they have a low molecular weight hence are excreted before reaching targeted sites. In this study, an attempt to improve the efficiency was done by providing carbon nanotubes (which were synthesized in our laboratories) as delivery systems. By conjugating bisphosphonates onto carbon nanotubes the molecular weight was increased. Bisphosphonates conjugated carbon nanotubes have been radiolabelled to increase their anticancer activity. By exploiting the Enhanced Permeability Retention (EPR) effect and the high energy electrons from the radioisotope (³²P), it is anticipated that bone metastasis will be successfully treated by the ³²P labelled bisphosphonates carbon nanotube conjugates. Successful synthesis of bisphosphonates conjugated carbon nanotubes was confirmed by several characterization techniques namely: the Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM), Raman spectroscopy, Thermal Gravimetric Analysis (TGA), Electron Dispersive X-ray (EDX), and the Fourier Transmission Infrared spectroscopy (FT-IR). Oxidation and bisphosphonates conjugation onto carbon nanotubes were further confirmed by the Raman, TGA, FT-IR, EDX and the SXPS (Scanning X-ray photoelectron spectroscopy) Successful radiolabelling was determined by a liquid scintillation counter (LSC).
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The efficacy of astragalus membranaceous tincture at maintaining the circulating leucocyte and absolute neutrophil counts of breast cancer patients undergoing chemotherapeutic treatmentMinnaar, Carrie-Anne 08 April 2010 (has links)
M. Tech. / AIM: To determine the efficacy of Astragalus membranaceous tincture at maintaining the circulating white blood cell count (WBC) and absolute neutrophil count (ANC) of breast cancer patients receiving chemotherapy. METHODS: This is an open-label study with an active control group. Both the study and control group consisted of fifteen participants. The participants in the study group each received ten millilitres of Astragalus membranaceous 1:2 tincture daily for the duration of their course of chemotherapy. RESULTS: The overall decrease in the WBC and ANC in the control was 4.9 and 3.13 parts per billion per litre, respectively. The study group showed an overall decrease of 2.7 and 1.9 parts per billion per litre, respectively. The average overall reduction in chemotherapy dose was 4.79 percent in the study group and 20.21 percent in the control. In all of the analyses p > 0.05. The small sample size, poor patient compliance and skewed distribution of the variables hindered the reliability of the results. CONCLUSION: The positive effects observed in the study group cannot be extrapolated to the entire population, however further research is strongly motivated.
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Proteome signature of breast cancer cells treated with fucoidanJanodien, Fatima January 2016 (has links)
>Magister Scientiae - MSc / Breast cancer is responsible for a large portion of cancer-related deaths. Worldwide, incidence is increasing. Routinely-used treatments for breast cancer are invasive and are associated with a range of side-effects which may affect quality of life. Fucoidan, a marine bioactive compound, found primarily in brown seaweed, has various medicinal qualities. Among its bioactivities studied, it has potent anticancer activity. Despite numerous studies, the mechanism of action of fucoidan on cancer cells remains unclear. This project aims to shed light on the mechanism of action of fucoidan by studying its effect on the MCF7 breast cancer cell proteome. The IC50 obtained for fucoidan treated MCF7 cells was 0.2 mg/ml. Decrease in expression of XIAP and phosphorylation of ERK1/2 was observed, indicating a decrease in inhibition of apoptosis and increased sensitivity to apoptosis, respectively. Literature reports activation of several caspases, including caspase-3, in various cell lines after to fucoidan treatment. Taken together, with data from the current study it can be said that fucoidan treatment led to cell death by apoptosis. SILAC analysis identified over 2000 proteins with more than 1700 at 95% confidence. STRING analysis of enriched proteins revealed 19 cell death related proteins. However, SILAC results were ambiguous with regards to differential protein regulation and should be repeated with lower electrospray ionization flow rates, pairwise and single sample runs, and validation with Western blot analysis of various apoptosis related proteins and biochemical assays. / National Research Foundation
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Complexing ability and activity of N-containing bisphosphonates in bone cancer treatmentCastelo Branco, Jose Soares 11 June 2008 (has links)
The nitrogen-containing bisphosphonates (N-BPs), 4-amino-1-hydroxy-1,1-butylidenebisphosphonic acid, or Alendronate, (ALN) and 6-amino-1-hydroxy-1,1-hexylidenebisphosphonic acid, or Neridronate (NED), were studied with metal ions Mg(II), Ca(II), Cd(II) and Pb(II) at ionic strength 0.15 M at 25 oC in NaCl. The complexes of ALN and NED with Mg(II) and Ca(II) were studied by glass electrode potentiometry (GEP), and with Cd(II) and Pb(II) by sampled direct current polarography (DCP) and normal pulse polarography (NPP) at fixed total ligand to total metal concentration ratios and varied pH values. Virtual potential was used in the modelling of the metal ligand-system derived from DCP and NPP. Protonation constants and complex formation constants for ligands ALN and NED with metal ions are reported. The structures of metal-complexes proposed were compared to the reported crystal structures of the metal-complexes of the ligands ALN and NED. The linear free energy relationships (LFER) that include stability constants log KML for Mg(II), Ca(II) and Cd(II) with ligands ALN and NED were used to estimate log KML values for Sm(III) and Ho(III) with ALN and NED. The stability constants estimated here might be regarded as not reliable due to the few points available for that purpose. / Dissertation (MSc (Chemistry))--University of Pretoria, 2008. / Chemistry / unrestricted
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Synovial sarcoma : translating gene expression into patient careTerry, Jefferson 05 1900 (has links)
Synovial sarcoma is a soft tissue tumor defined by the presence of t(X;18)(p11.2;q11.2), fusing the SYT (SS18) gene on chromosome 18 and one of three SSX genes on chromosome X. T(X;18) results in production of a fusion protein (SYT-SSX) that is thought to underlie synovial sarcoma pathogenesis through aberrant targeting of both activating (trithorax, SWI/SNF) and repressing (Polycomb) transcription factors when expressed in a stem or progenitor-like cellular background.
Clinically, synovial sarcomas present considerable diagnostic and therapeutic challenges. Whereas the classical biphasic histology is distinctive, the more common monophasic histology can be difficult to differentiate from other spindle cell tumors. In these situations, detection of t(X;18) is the gold standard for diagnosis, but it is a specialized and time-consuming process. Immunohistochemistry can be helpful, but no marker that is both highly sensitive and specific is available. Here I describe a fluorescence in situ hybridization based method employing an SYT break-apart probe set that can expedite detection of t(X;18). I also report that TLE1, which was identified in gene expression studies as a good discriminator of synovial sarcoma from other mesenchymal tumors, is a highly sensitive and specific immunohistochemical marker for synovial sarcoma. Both of these novel diagnostic techniques are applicable to small tissue samples such as core needle biopsies and are now being used clinically.
The diagnosis of synovial sarcoma carries a poor prognosis and the 10-year overall survival rate is approximately 50%, most of whom are young adults. The addition of chemotherapy to surgical resection (the mainstay of treatment) does not appear to improve overall survival. Thus, there is a strong need for development of a clinically effective systemic therapy to improve patient outcome. I describe preclinical studies that demonstrate the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits proliferation of synovial sarcoma by inducing apoptosis and that this is associated with degradation of multiple receptor tyrosine kinases and disruption of the SYT-SSX-β-catenin interaction. I also identify a subset of synovial sarcoma cells, typified by expression of CD133, which exhibit stem-like properties and are relatively resistant to doxorubicin but susceptible to 17-AAG at clinically relevant concentrations. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate
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