A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements of the degree of Masters of Science. February 2017. / Cancer has become a problematic fatal disease in developing and industrialised countries with pancreatic cancer as the seventh leading cause of cancer-related deaths, with an average survival rate of less than 5%. Environmental risk factors associated with pancreatic cancer include smoking, obesity, diet, alcohol etc. Furthermore, pancreatic cancer is commonly diagnosed at a late stage where its response to current anti-cancer agents is poor. Consequently, with South Africa being a 3rd world country and the cost of chemotherapy being so high, this has led to us trying to identify new, cheaper therapeutics for cancer cells. A majority (80%) of the South African population relies on traditional medicines, hence in this study we aimed to assess Lobostemon fruticosus for anti-proliferative effects on pancreatic cancer cell line (AsPC-1). This was achieved by the use of methanol and butanol extracts of L. fruticosus to screen for induction of apoptosis and inhibition of cell proliferation. The plant was collected, dried, crushed and dissolved in butanol and methanol to obtain experimental extracts. Cytotoxicity of the plant on Aspc-1 was determined using MTT Assay, xCELLigence and cell cycle analysis. MRC-5 cell line was used as a positive control cell line. L. fruticosus extracts induced cell death at IC50 of 60µg/ml (methanol extract) and 50µg/ml (butanol extract) at 48hour treatments on AsPC-1 cell line. Western Blots showed that the methanol and butanol extracts of L. fruticosus led to slight upregulation of the apoptotic gene p53 in AsPC-1 cell line, which was further confirmed by FACS apoptosis detection. Cell cycle analysis further showed the plant extracts do promote cell cycle arrest. LC/MS of the extracts gave spectra of active compounds presumed to play a role in induction of apoptosis on the pancreatic cancer cell line. The data obtained implies that the methanol and butanol extracts of L. fruticosus does have, to a certain extent, growth inhibiting and apoptosis inducing potential on the pancreatic cancer cell line. KEYWORDS: Lobostemon fruticosus, Pancreatic Cancer, methanol extract, butanol extract, AsPC-1 / LG2017

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Master of Science June, 30, 2015 / The world suffers under a serious threat of malaria with about 584 000 deaths reported each year and most of these fatalities being children under five years of age. Malaria is caused by the protozoan parasite of the genus Plasmodium. Five different malaria species infect humans and cause disease: P. vivax, P. malariae, P. ovale, P. knowlesi and the cause of most malaria deaths, P. falciparum. The main reason for this disturbing situation is the emergence of drug resistance which reduces the effectiveness of most antimalarials. Hence, there is an urgent need for new drugs that will possibly be effective against both wild type and mutant strains of Plasmodium species. Pyrimethamine, a dihydrofolate reductase (DHFR) inhibitor, has been used most widely as an antimalarial antifolate drug for the treatment of malaria. However, rapid development of parasite resistance to this drug occurred because of its rigidity. Parasitic resistance to antimalarial antifolates arises from single mutations at various amino acid residues surrounding the PfDHFR active site. In this project, we aimed to design and synthesise a novel series of flexible pyrimidine analogues of a dihydrotriazine hit compound prepared in a previous study. These compounds were designed to target folate metabolism in the malaria parasite. The initial series of compounds prepared in this project were synthesised over 5 steps in an overall yield of 10%. The flexible pyrimidine analogues were screened for antimalarial activity in an in vitro P. falciparum screen on the Gambian FCR-3 strain (chloroquine and cycloguanil resistant strain) with dihydroartemisinin, methotrexate and quinine as controls. 5-(3-(3,5-Dichlorophenoxy)propyl)-6-phenylpyrimidine-2,4-diamine displayed the best antimalarial activity (IC50 = 0.09 μM) of the compounds in this series. Surprisingly; this was the only compound prepared in this series that proved to be as effective as our original hit dihydrotriazine (IC50 ~50 nM). In the second generation of compounds prepared in this study, we used a multicomponent coupling approach to synthesise three flexible pyrimidines bearing a non-aromatic side chain at the 6-position of the pyrimidine ring. For comparison, two analogues bearing a phenyl group at the 6-position of the pyrimidine ring were also prepared. Once again; only one compound of this series [5-((4-chlorophenethylamino)methyl)-6-cyclopropylpyrimidine-2,4-diamine, (IC50 = 0.03 μM)] showed activity comparable with our original hit compound. iv Finally, ten substituted pyrimidines bearing a flexible side chain at the 6-position of the pyrimidine ring, were prepared. These compounds are structurally similar to P65, [6-methyl-5-(3-(2,4,5-trichlorophenoxy)propoxy)pyrimidine-2,4-diamine] an analogue of a potent antifolate, WR99210, found to have good oral bioavailability in rats. Once again, the antimalarial activity of the compounds prepared was assessed in an in vitro P. falciparum screen on the Gambian FCR-3 strain. The most promising compound of this series was 6-(3-(3,4-dichlorophenoxy)propoxy)pyrimidine-2,4-diamine, which exhibited antimalarial activity in the low micromolar range (IC50 = 4.46 μM).

M.Med., Faculty of Health Sciences, University of the Witwatersrand, 2009 / Objectives Cancer of the cervix is one of the commonest cancers in South African females. Up to 30% of patients are HIV positive. The addition of chemotherapy to radiotherapy has been shown to significantly improve local control and survival and concurrent chemoradiation is the standard treatment for locally advanced cancer of the cervix. There is very limited literature available concerning the tolerance and efficacy of this treatment in HIV positive patients. This study aims to assess the acute toxicity of combined modality treatment in these patients. This study is part of a multicenter International Atomic Energy Agency sponsored study. Materials and methods Patients with FIGO stage IB2 to IIIB (without hydronephrosis) cervical cancer and who are HIV positive, were randomized to receive radiotherapy alone or chemo-radiation. All patients received 46 Gy in 23 fractions external beam radiation and high-dose-ratei brachytherapy 8 Gy x 3 fractions. Chemotherapy consisted of bolus Cisplatin 30mg/m2 weekly given concurrently with the radiotherapy. Acute treatment toxicity was documented weekly during treatment. Results 64 patients were recruited to the study. 31 patients were randomized to the chemoradiation arm and 33 patients to the radiation alone arm. Of the 64 patients recruited to the study, 6 in the chemoradiation arm and 5 in the radiation only arm did not receive any treatment and were therefore not evaluated. Stage IIB was the most common stage. The mean CD4 count was 410 in the chemoradiation arm vs. 358.4 in the radiation only arm at randomization. Only 6 patients were on antiretroviral therapy at start of treatment, 3 in each arm. The number of chemotherapy cycles received by patients in the chemoradiation arm ranged between 0 and 5 cycles. A total of 96 chemotherapy cycles were administered, with a median of 4 cycles per patient. Overall, at least 76% of patients received at least 4 cycles of chemotherapy. The full five intended courses of cisplatin were administered in 10 (40%) patients. Chemotherapy was not administered most commonly due to toxicity (renal, leucopaenia), other reasons being logistical and non compliance. The principle major adverse effects observed were leucopaenia and cutaneous reactions.

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy of Science. Johannesburg, 2013 / Chemotherapy, while representing a vital component of cancer treatment modalities, has so far not fulfilled basic expectations with unsatisfactory cure rates and frequent relapse due to limited effectiveness of the therapeutic drugs, severe side effects and resistance problems. The platinumcontaining drugs used in present clinical practice are no exception to this generalized finding. While highly effective against a small number of malignancies, they generally share in the deficiencies of other anticancer agents. To address this issue, intense research is being undertaken to develop novel platinum-compounds offering enhanced therapeutic effectiveness. To accomplish this, several new avenues of development are being pursued world-wide, and one of these involving the binding of monomeric anticancer drug systems to water-soluble, biocompatible and biodegradable polymeric carriers, was utilized in the current research. As part of the ongoing research, this dissertation demonstrates the preparation of several water-soluble polymeric carriers bearing pre-synthesized monomers aimed to anchor the platinum drug. The monomers of interest were aspartic acid, p-aminobenzoic acid and p-aminosalicylic acid derivatives; while the water-soluble carriers were polyaspartamides, prepared by an aminolytic ring-opening process of polysuccinimide. The platination agents were conjugated to the polymer backbone both via amine and via leaving-group ligands, such as dihydroxylato, dicarboxylato and carboxylatohydroxylato. In order to demonstrate the multidrug-binding capacity of the carriers, platinum complexes were co-conjugated to polymeric conjugates containing ferrocene. The in vitro studies against a human breast cancer (MCF-7) cell line showed IC50 values ranging from 48.92 μg.mL-1 to 281.37 μg.mL-1 for the platinum conjugates, 13.18 μg.mL-1 to 149.67 μg.mL-1 for ferrocene conjugates and 6.22 μg.mL-1 to 83.86 μg.mL-1 for platinum/ferrocene co-conjugates; and these values were on average 4 fold more active than the parent drug. The results of these preliminary tests provide proof of the principle that polymer-drug conjugates can play a role in future cancer therapy.

Orientador: María del Pilas Taboada Sotomayor / Banca: Maria Valnice Boldrin Zanoni / Banca: Assis Vicente Benedetti / Banca: Regina Massako Takeuchi / Banca: Karin Yanet Chumbimuni Torres / Resumo: Neste trabalho é apresentado o desenvolvimento de dois sensores eletroquímicos modificados para determinação sensível e seletiva de cisplatina, um dos fármacos mais frequentemente utilizados no tratamento oncológico de diversos tipos de patologias tumorais cancerosas. O primeiro sensor foi desenvolvido a base de pasta de carbono modificado com a enzima glutationa-s-transferase (GST). O biossensor é baseado na resposta inibitória da atividade enzimática da enzima GST devido à adição do fármaco cisplatina. Glutationa reduzida (GSH) e 1-cloro-2,4-dinitrobenzeno foram utilizados como substratos para a enzima GST, os quais foram adicionados na concentração de 1,0 x 10-3 mol L-1 na cela de medida. As técnicas utilizadas para a caracterização do sistema foram espectroscopia de infravermelho, voltametria cíclica e impedância eletroquímica. Os resultados quantitativos daquelas interações foram obtidos usando VOQ, observando-se uma resposta linear entre 50 e 140 μmol L-1 de cisplatina e limite de detecção de 8,8 μmol L-1 de cisplatina. O biossensor apresentou uma boa repetibilidade intra-dia com um desvio padrão relativo de 4,2% avaliando quatro curvas analíticas. O uso da pasta de carbono ofereceu a possibilidade de uma simples, rápida e eficiente renovação da camada de superfície do eletrodo, o que permitiu a utilização da mesma pasta em várias medidas durante um longo período de tempo. Adicionalmente, foi desenvolvido um sensor não enzimático no monitoramento da cisplatina usando eletrodos impressos de carbono (SPCE, screen-printed carbon electrodes) modificados com nanotubos de carbono de multiplas paredes funcionalizados com grupos carboxila (MWCNT-COOH.SPCE) da DROPSENS® (SDS 110CNT). Com o propósito de avaliar a influência dos nanotubos de carbono na resposta do sensor de cisplatina foi utilizada a técnica de voltametria cíclica. O uso do surfactante dodecilsulfato... / Abstract: This thesis presents the development of two electrochemical sensors for the sensitive and selective detection of cisplatin, one of the drugs most frequently used in the oncologic treatment of several cancer tumor pathologies. The first was a biosensor based on carbon paste modified with the enzyme glutathione-s-transferase (GST). The biosensing was based on the inhibitory response of the enzymatic activity of GST due to the addition of the drug cisplatin. Reduced glutathione (GSH) and 1-chloro-2,4-dinitrobenzene were used as substrates for the GST enzyme, and were added at the concentration of 1.0 x 10-3 mol L-1 in the measuring cell. The techniques used for the characterization of the system were infrared spectroscopy, cyclic voltammetry and electrochemical impedance. The quantitative results of those interactions, obtained by square wave voltammetry (SWV) and differential pulse with adsorptive stripping voltammetry were very similar, and very promising for the analysis of cisplatin. The biosensor showed, using SWV, a linear response between 50 and 140 μmol L-1 of cisplatin. The detection limit was 8.8 μmol L-1 of cisplatin. In the intra-day repeatability studies, the relative standard deviation was 4.2%, from the analysis of four analytical curves, showing the repetitiveness of the electrochemical response of the proposed sensor. The use of the carbon paste offered the possibility of the simple, quick and efficient renewal of the surface layer of the electrode, which allowed the use of the same paste for several measurements during a long period of time. Additionally, a non-enzymatic sensor was developed for the monitoring of cisplatin using screen-printed carbon electrodes (SPCE, screen-printed carbon electrodes), functionalized with multi-walled carbon nanotubes and factory modified with carboxyl groups (MWCNT-COOH) acquired from DROPSENS® (SDS 110CNT). The electrochemical characterization... / Doutor

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Purpose: The proportion of the United States population in older adulthood is growing rapidly, and with that growth comes an increase in diseases such as cancer. As rates of illness increase, there is a concomitant increase in cognitive and psychological correlates of illnesses like cancer. There is evidence that some cancer treatments, particularly chemotherapy, affect cognition for cancer patients, although these results are inconsistent. Additionally, depression, and other health factors such as activities of daily living (ADLs) have been found to relate to cognitive impairment among older adults with cancer. Method: The current study used latent class growth analysis (LCGA) to explore longitudinal data from the Health and Retirement Study. The primary goal was to investigate possible trajectories of cognitive functioning in older adults diagnosed with, and surviving cancer. Possible psychological, health, and demographic predictors of membership in these cognitive trajectories were investigated. Results: Findings indicated that three classes of cognitive functioning best fit the data: these were High Recall, Middle Recall and Low Recall Classes, which represented fairly stable trajectories from pre-diagnosis to a period four years later. Various covariates of class membership were included in the analyses. Treatment with chemotherapy significantly predicted membership in the High Recall Class, however this finding is accounted for by an interaction with younger age. More symptoms of depression after diagnosis (but not prior to diagnosis) were significantly predictive of membership in the Low Recall Class. A higher self-reported probability of living to the age of 85 pre-diagnosis predicted membership in the High Recall Class, and greater difficulty with ADLs post-diagnosis predicted membership in the Low Recall Class. Finally, individuals in the High Recall Class were significantly more likely to be younger, female, and more highly educated, when compared to both the Middle and Low Recall Classes. Limitations: The current study is limited by the wide spacing of data collection and dearth of sensitive and varied measures of cognitive functioning, which in turn limits the generalizability and specificity of the findings. Additionally, a lack of data on cancer type, staging and treatment variables make more nuanced analysis difficult. It is not possible to generalize these findings to individuals who passed away within two years of their diagnosis, not to individuals of minority status, who were underrepresented in this sample. Conclusions: These results may inform the understanding of cognitive functioning in older adults surviving cancer, as it relates to psychological, demographic and other health factors, with implications for timing and targeting of interventions.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Cancer‐related fatigue (CRF) is a well‐documented symptom among gynecologic oncology patients. However, there is little known about the etiology, and treatment options are currently suboptimal. While the lack of knowledge surrounding the intricacies of CRF impedes effective care, there is arguably a more serious barrier to delivering adequate treatment. Fatigue symptoms are highly underreported to physicians making it impossible to offer treatment to a large subsection of patients. This study will focus specifically on gynecologic oncology patients, a population with a staggering prevalence of CRF. The purpose of this study is to identify clinical, psychosocial, and lifestyle characteristics that may be associated with the underreporting of fatigue specifically in gynecologic oncology patients. The design of this study is a cross‐sectional survey. 89 subjects were recruited from three outpatient sites. Inclusion criteria included: (a) women age ≥18 years old with a known ovarian, uterine, cervical, vaginal, vulvar, or primary peritoneal cancer; (b) Currently attending physician’s office hours and/or undergoing chemotherapy at one of the above listed centers. This study will focus specifically on the reporting of CRF in gynecologic oncology patients. Results showed that barriers to reporting fatigue were significantly correlated with the chemotherapy cycle a patient was undergoing. Additionally, the date of last treatment, a patient’s weight, and the cancer stage was associated with higher levels of underreporting in this population. The prevalence of cancer related fatigue is staggering; however, there is limited research as to why patients are underreporting such a significant symptom to their health care team. With the knowledge from this study, screening for fatigue can become more efficient by targeting women in specific chemotherapy cycles. Practitioners can also use this data to identify patients with high‐risk characteristics that might contribute to their unwillingness to discuss fatigue symptoms.

No description available.

Policy-makers, funding bodies and treatment providers need current, comparable and accurate information on the activities and outcomes of alcohol and other drug (AOD) treatment services to respond to the needs of the sector. If meaningful comparisons are to be made at the jurisdictional level, a standardised treatment outcome monitoring system must be developed and implemented, that takes into account differences in client characteristics, treatment settings and modes of service provision. A brief, multi-dimensional instrument, the Brief Treatment Outcome Measure (BTOM) has been developed for routine, ongoing treatment outcome monitoring with clients receiving opioid maintenance pharmacotherapy (OMP) services in New South Wales (NSW), and for use in treatment evaluation research. This is the first time in Australia that an attempt has been made to integrate outcome monitoring into routine clinical practice across an AOD treatment sector. The BTOM contains thirty-three items across the domains of dependence, blood-borne virus exposure risk, drug use, health/psychological functioning and social functioning. The internal reliability of the BTOM is satisfactory; retest reliabilities for the measures are good to excellent and concurrent validation of BTOM scales yielded acceptable agreement. Average completion times of the BTOM were 14.5 minutes when administered by researchers and 21 minutes by clinicians. A 30-month feasibility trial was conducted in selected NSW OMP treatment agencies to determine the practicability of implementing an OMS; to identify issues that would impact on the quality of the data; and identify administrative processes that could facilitate implementation whilst minimising the burden on agency staff. In addition, clinicians who had administered the BTOM were surveyed 18 months into the trial to ascertain their attitudes towards the clinical utility, acceptability of content and the level of support given to them to administer the BTOM as part of routine clinical practice. Results from the trial indicate that the BTOM measures are sensitive to change over time; that the change observed is consistent with that reported in the OMP treatment outcome literature; and that clinicians, whilst generally being positively predisposed towards using the instrument, express concerns relating to the burden of administering and the clinical utility of conducting outcome monitoring.