The research conducted in this study focussed on advancing the knowledge database of diamineplatinum complexes on two frontiers: 1) the development of novel anticancer complexes, and 2) improvements in their synthetic chemistry. Novel square-planar dichloro and oxalato platinum(II) complexes were synthesized as potential anticancer agents in accordance with a comprehensive set of factors identified as being significant in optimizing such action. The nonleaving ligands consisted of asymmetric chelating chiral diamines of the form 1- (1-R-imidazol-2yl)(R')methanamine (R representing methyl, butyl and R' methyl, phenyl). The complexes were characterized by a host of spectral, thermal and crystallographic techniques. In addition, the stabilities of the complexes were monitored in aqueous and saline solutions. Cytotoxicity screening on three cultured cancer cell lines (MCF-7, HeLa and HT29) indicated the compounds, present as their respective racemates, to have rather modest activities relative to cisplatin; with complexes having the smallest substituents, R,R' = methyl, being most active. In recognition of the limitations of traditional silver-based syntheses of oxalatoplatinum(II) complexes, innovative non-silver methods were developed using the well known cancer drug, oxaliplatin, (trans-R,R-1,2- diaminocyclohexane)oxalatoplatinum(II), as a prototype. These involved direct ligand exchange reactions of the dichloro precursor, (trans-R,R-1,2- diaminocyclohexane)dichloroplatinum(II), with tetrabutylammonium oxalate in essentially non-aqueous solvents. A 90:10 mixture of isoamyl alcohol (3-methyl- 1-butanol):water, proved to be a promising solvent, enabling the recovery of pure oxaliplatin (~98 percent) after 9 hours at 88 °C in yields of up to 86 percent. In light of the perceived unique mode of anticancer action available to mononitroplatinum(IV) complexes (i.e. their STAT3-binding potential), octahedral diamineoxalatoplatinum(IV) complexes containing axially-coordinated nitro and halo co-ligands were synthesized and extensively characterized. Electrochemical studies revealed trends in reduction potential which could be correlated to structural / chemical traits of the coordinated diamine and axial ligands. The similarities of the determined cytotoxicities of the platinum(IV) compounds and their respective platinum(II) analogues, implicated reduction as a means of activation of the platinum(IV) complexes.

Complaints of reduced cognitive abilities are frequent following chemotherapy. Research in the breast cancer population has revealed some patients may experience treatment-related decline in cognitive domains such as executive function, information processing speed, memory and learning, attention and concentration, and working memory. The extent and mechanism of action of this phenomenon remain poorly understood. Neuroimaging research can characterize the neural underpinnings of chemotherapy-related cognitive impairment; however, with few longitudinal studies, more prospective studies are needed to elucidate this important topic. The aim of this thesis was to use magnetic resonance imaging and contemporary analysis techniques to better understand the influence chemotherapy exerts on both the brain and cognition. This was achieved in two studies that measured cognitive function and brain structure and function at three time points: pre-treatment, one month post-chemotherapy, and at one-year follow-up. In the first study, the association between regions of brain structural changes and cognitive function was examined. The second study took a narrower approach and investigated the functional profile of brain activity during a working memory task. Patients had more pronounced structural and functional disruptions shortly after treatment, relative to both pre-treatment and one-year post-chemotherapy intervals. Regions of structural compromise were largely associated with information processing speed. Functional disruptions occurred in a frontoparietal network. Overall, this thesis provides more evidence of the injurious role chemotherapy plays on cognition, particularly in the short term. This thesis also provides the first longitudinal neuroimaging study to illustrate a complete resolution of working memory related brain disruption one year post-treatment.

Major advances in antiemetic therapy have been made over the past two decades. Despite these advances in antiemetic management, nausea and vomiting are still important problems in clinical practice, and approximately 50% of patients receiving chemotherapy still experience nausea and/or vomiting, highlighting the need for further developments in the field. Non-pharmacological interventions are suggested as possible adjuncts to standard anti-emetic therapy. A recently developed non-pharmacological intervention to alleviate nausea and vomiting is Nevasic, which may have potential to reduce CINV and improve management of these symptoms.This pilot trial was run to examine the feasibility of implementing and conducting a randomised controlled trial using Nevasic programme. In addition, the study aimed to evaluate the acceptability and potential effect of Nevasic on cancer patients undergoing chemotherapy. Ninety nine adult female breast cancer patients who had been prescribed a course of moderately high emetogenic chemotherapy were randomised to usual care (standard anti-emetics) plus one of (1) intervention group (using Nevasic), (2) attention group (listening to music), and (3) control group, receiving no additional intervention. Data were collected daily using the Rhodes Index of Nausea, Vomiting and Retching (INVR) and a structured diary questionnaire. The EORTC QLQ-C30 (and BR23) were used at baseline and day 6 post chemotherapy. Data were collected from cancer centres affiliated to Mashhad University of Medical Sciences in Mashhad, Iran.The findings from the trial highlight that conducting a non-pharmacological intervention using such an audio programme is feasible, although difficulties and limitations exist. This study did not detect any evidence for the effectiveness of Nevasic on CINV; however, the results show statistically significant less use of anti-emetics (post-chemotherapy) (p=0.03) and borderline non-significant (p=0.06) better global health status in Nevasic group. Further studies are required to investigate its implications from other perspectives such as use of anti-emetics - rather than looking only at the "level of nausea and/or vomiting" perspective.

The present thesis, entitled Chemotherapy-induced cognitive changes, is being submitted in the alternative format, by Oana Calina Lindner to The University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences, School of Psychological Sciences. The thesis consists of five empirical studies, written in article formats and three connecting chapters. The General introduction in Chapter 1, places the thesis in the context of late effects research in cancer survivors. I describe the prevalence of physical and emotional late effects, before going into more details on cognitive late effects. Chapter 2 provides a meta-analytical summary of cognitive impairments following chemotherapy in adult patients. It has already been published in Neuropsychology in 2014. Chapter 3 describes the general objectives and hypotheses of the empirical studies, and Chapter 4 provides more details on the General methods utilized in all the studies. The studies focus on pre- and post-treatment young adult cancer patients who were compared to age-, sex-, and education-matched controls. The instruments include a comprehensive neuropsychological battery, a newly designed memory task, and a complex battery of self-assessment questionnaires. Chapter 5 is the first empirical study, which will be submitted to Journal of Clinical Oncology. It describes the pattern of neuropsychological status of young adult cancer patients following treatment for lymphoma, sarcoma, breast cancer, and germ cell tumour. The impairments were specific to executive functioning, verbal memory, and visuospatial abilities. Uniquely, the chapter depicts differences between cancer groups. Because chemotherapy may not be the primary factor triggering such effects, Chapter 6 details the neuropsychological profile of a group of young adult pre-treatment patients diagnosed with the same malignancies. This chapter will be submitted to Journal of Neuropsychology. Impairments were observed on tests of attention, executive functioning and visuospatial abilities. Both Chapters 5 and 6 emphasize the importance of matching on full scale IQ in cross-sectional studies and they provide evidence that patients' performance on tests of verbal memory and executive functioning may vary as a function of age. Chapter 7 will be submitted to Psycho-Oncology and it suggests the presence of acute memory deficits after the first treatment. Finally, Chapter 8, which will be submitted to Psychosomatic Medicine, provides an in-depth description of the psycho-emotional status of cancer survivors. It describes higher levels of anxiety, depression, fatigue, and cognitive complaints, which mediated the relationship between illness perceptions and quality of life. The complex interaction between these psycho-emotional factors is interpreted within the framework of cognitive-behavioural therapies, which may provide a method to decrease the emotional burden of survivorship in clinical practice. Finally, Chapter 9 summarizes all the empirical findings whilst connecting them to previous literature and specifying future research direction.

Malaria is a global health threat that causes 300 – 500 million clinical cases annually, resulting in approximately 2 million deaths. Chemotherapy and prophylaxis are becoming less effective because of increasing drug resistance by the parasite. Resurgence of malaria calls for the development of mechanistically novel drugs. The bifunctional organization of the two rate-limiting enzymes, AdoMetDC and ODC, in the P. Falciparum polyamine pathway and the presence of six parasite-specific inserts, present potential target sites for novel Plasmodia-specific drugs. The inserts are species-specific, hydrophilic, low complexity segments and form non-globular domains. The inserts are involved in intra- and interdomain interactions, which are important for stability and activity of the bifunctional construct. This study investigated properties of the parasite-specific inserts, one being the mobility of the O1 insert and the other the secondary structures present in the parasitespecific inserts. It is postulated that the mobility of the O1 insert plays a role in either heterotetrameric complex formation of the bifunctional construct or that the O1 insert acts as a “lid” to the ODC active site, which is necessary for catalytic function. Successful mutagenesis of the O1 flanking Gly residues to Ala, rendered the O1 insert immobile. The probable immobility of the O1 insert had a detrimental effect on the activity of both the AdoMetDC and ODC domains of the bifunctional protein. Molecular dynamics studies showed that movement restriction of the insert caused a conformational change in the ODC monomers. The decrease of both domain activities upon movement restriction of the O1 insert suggests that the insert is involved in protein-protein interactions, which is communicated throughout the protein. In addition, the roles of selected, predicted secondary structures in the Hinge, O1 and O2 parasite-specific inserts were investigated. á-Helices were disrupted by the introduction of a Pro residue, â-plates were removed with deletion mutagenesis. The effects of the secondary structure alterations on protein activity were monitored in the bifunctional PfAdoMetDC/ODC protein. Both domain activities were affected by the disruptions, although the ODC domain was more sensitive to the small changes. The results obtained in this study showed that the secondary structures in the parasite-specific insert are important for activity of both the AdoMetDC and ODC domains of the bifunctional protein, possibly via interdomain protein-protein interactions. The delineation of essential intra- and interdomain protein-protein interactions presents possible interaction sites for disruptive molecules in the combat against malaria. Copyright / Dissertation (MSc)--University of Pretoria, 2009. / Biochemistry / unrestricted

Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) are hematologic malignancies that occur most frequently in the sixth and seventh decades of life. Both disorders are associated with a poor prognosis, with median survival of one year or less. An overall five-year survival rate for both disorders, regardless of treatment, is less than 10%. A primary goal of treatment is to improve quality of life (QOL) because cure is improbable. The purpose of this longitudinal cohort study was to compare QOL between groups, intensive, non-intensive therapy, and supportive care. The sample consisted of 85 patients with high risk MDS and AML recruited from Moffitt Cancer Center. Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) was used to measure QOL. The aims for the study were to: 1) To compare the difference in QOL scores measured by the Functional Assessment of Cancer Therapy –Leukemia version for intensive chemotherapy, non-intensive therapy and supportive care within 7 days of new treatment and one month after initiation of treatment; 2) To determine QOL predictors of AML and high risk MDS from age, comorbidity, fatigue, and diagnosis; 3) To test the moderating effect of treatment with age, comorbidity, and fatigue on QOL. The first aim was analyzed with repeated measures analysis of variance (ANOVA). The supportive care group was not included in the analysis because of low accrual. Results indicated that there was a significant group by time interaction (with p=.040). Follow up tests revealed that the intensive treatment group had a significant improvement in their QOL scores at 1 month post treatment (p=.020). The second aim was conducted using Pearson’s correlations with age, comorbidity, fatigue, and diagnosis with significant correlations found between fatigue and QOL (r=-.693, p< .001). These findings identify an important relationship between fatigue and QOL. This was a negative correlation, showing that as fatigue increases QOL decreases. The third aim was explored using regression with Hayes (2013) application for moderation analysis. Scores for QOL for age, comorbidity, and fatigue were not moderated by treatment. These findings suggest that the most intensive treatment approach improves QOL. In addition, fatigue is a significant predictor of QOL. As fatigue increases, QOL scores decrease. Additional studies with a larger, more diverse sample is needed to explore the relationship between treatment approaches and QOL. In addition, intervention studies can be developed in AML and high risk MDS focused on fatigue management. It is anticipated that the results of this study will be used to inform patients and health care providers when making decisions concerning treatment based on QOL outcomes.

BACKGROUND: Palliative chemotherapy is cancer-directed therapy, which aims at stopping or slowing down the progression of the malignancy even though it may not have any potential for remission or cure. In South Africa, delayed diagnosis of childhood cancer is a common problem for a variety of reasons including lack of health care facilities, transport, information about the disease and delayed presentation due to traditional healer visits or other cultural issues. In patients who present with advanced cancer, or in patients with relapsed cancer without realistic hope of cure, palliative chemotherapy can be offered in an attempt to manage symptoms, improve quality of life and prolong meaningful survival. OBJECTIVES: This research study evaluated South African paediatric oncologists' perspectives and practices regarding the use of chemotherapy in patients with cancer with no realistic hope of cure. The second part of the study described the use of palliative chemotherapy in patients who received treatment at the Steve Biko Academic Hospital Paediatric oncology unit. DESIGN & METHOD: An online survey was conducted among paediatric oncologists in South Africa. The main aims of the questionnaire were to assess paediatric oncologists' considerations around the use of palliative chemotherapy, and then focus on the most recent patients treated with palliative chemotherapy. For the second part of the study, a file review was done of deceased patients who died in the period from January 2012 to December 2018 and who had received palliative chemotherapy as part of their cancer management. We reviewed diagnoses, palliative chemotherapy regimens, timing of initiation and stopping palliative chemotherapy, and whether end of life decisions and discussions were documented. RESULTS: A total of 41 participants completed the survey, giving a response rate of 89%. The majority of the paediatric oncologists were either neutral or agreed that palliative chemotherapy should be considered. The most important treatment aim was to improve quality of life of the patient (92.7% of respondents). The most important considerations when prescribing palliative chemotherapy was to minimise toxicity of the chemotherapy regimen (4.56 mean, SD=0.5 utilising a 5 point scale where 1=not important to 5=very important), and the effectiveness of the chemotherapy (4.37; SD=0.48). Only 19.5% of patients received treatment primarily because parents requested it. According to the oncologists polled, the key considerations were largely achieved in the most recent patient treated with palliative chemotherapy. Individual opinions and preferences concerning recommending palliative chemotherapy differ between paediatric oncologists. Of the 305 patient deaths recorded in the study period, a total of 74 patients had received palliative chemotherapy and were included in the file review. The most common diagnoses were neuroblastoma (18.2%), retinoblastoma (15.6%) and osteosarcoma (14.3%). At the time of diagnosis, the median age of the patients was 6.0 years (range 0.3 to 17.6 years). In 47 patients (63.5%) the disease was deemed incurable at first diagnosis and palliative chemotherapy given from the onset of treatment, while 27 patients (36.5%) were given palliative chemotherapy at relapse. The median time from last palliative chemotherapy to death was 30 days (range 0-742 days). The main documented aim of palliative chemotherapy was to improve symptom control (97.3%) while parents' opinion played an important role in 32.9% of cases. About half of the patients (41 of 74, 55.4%) had documentation of symptomatic improvement. CONCLUSION: Although the overall attitude towards the use of palliative chemotherapy is positive, there is great inter-individual variation between oncologists in opinions and experience. The lack of empirical data to justify recommendations about palliative chemotherapy remains a problem, and the researcher hopes that this study will spark productive discussion and planning towards more structured use of palliative chemotherapy in children with cancer in South Africa. This study shows that many decisions around end of life care and decision-making could be better researched using a quantitative, prospective, interview-based approach. Repeated measurements of the child and family's quality of life and its associations with palliative chemotherapy should be a research priority in future.

No description available.

Thesis (M.Sc. (Biochemistry)) -- University of Limpopo, 2020 / Despite major advancements in the development of various chemotherapuetic agents, treatment for lung cancer remains costly, ineffective, toxic to neighbouring normal noncancerous cells and still hampered by high level of remissions (Wistuba et al., 2018; Tana et al., 2016; Schiller et al., 2002). Synthesis of novel quinoxalines with a wide spectrum of biological activities has recently received considerable attention with promising anticancer drug activity since most of them do not affect non-cancerous cells and are derived from readily available less costly raw materials (Srivastava et al., 2014). Since combination treatment has been shown to augment and improve single drug treatment, trace elements were employed in this study in combination with quinoxalines derivatives (Gomez et al., 2016; Kocdor et al., 2015; Ku et al., 2012; John et al., 2010; Killile and Killilea, 2007). Zinc is an essential element that is integral to many proteins and transcription factors which regulate key cellular functions such as the response to oxidative stress, DNA replication, DNA damage repair, cell cycle progression, and apoptosis (Dhawan and Chadha, 2010). Owing to the importance of these two approaches, the aim of this study was to provide in vitro preliminary anticancer activity data on A549 lung cancer cells using combination of zinc and quinoxaline derivatives. An assessment of the quinoxaline derivatives ferric reducing power and DPPH free radical scavenging activity was performed. The cytotoxic and anti-proliferation activity of these derivatives and zinc on cancer cell lines was determined using the MTT assay. The ability of the quinoxaline derivatives and zinc to modulate oxidative stress was evaluated using the H2DCFDA fluorescence assay. Cell cycle arrest stages were analysed by flow cytometry through propidium iodide cell cycle analyses. The ability of the quinoxaline derivatives to induce apoptosis in cancer cells was assessed using DAPI/PI, Acridine Orange/Ethidium Bromide (AO/EB) and Annexin V-FITC/Dead Cell assays. Western blot was used to investigate the Bcl/Bax expression ratios in A549 lung cancer cells after treatment with quinoxaline derivatives, zinc and in combination. Of the four quinoxaline derivatives tested, 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate (LA-39B) and 3-(quinoxaline-3-yl) prop-2-yn-1-ol (LA-55) produced significant anticancer properties against A549 lung cancer cells at minimal concentrations of 25μM. Both quinoxaline derivatives displayed antioxidant properties and did not induce cell death in non-cancerous Raw 267.4 macrophage cells. Cytotoxicity was observed in A549 lung cancer, HeLa cervical cancer and MCF-7 breast cancer cells albeit inhibition was more pronounced in A549 lung cancer cells. Treatment of cancer cells with zinc also resulted in pronounced cytotoxicity at a minimal concentration of 25μM. Although reduced oxidative stress was observed in Raw 264.7 macrophages, in A549 lung cancer cells both compounds were able to increase ROS production which was accompanied by high levels of apoptosis when treated with derivatives and zinc alone but when in combination an improved higher level of apoptosis is observed. The improved anti-cancer activity of this drug combination treatment was further accompanied by lower Bcl/Bax expression ratios with upregulation of Bax in A549 lung cancer cells. The results of the study suggest that 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate and 3-(quinoxaline-3-yl) prop- 2-yn-1-ol are potential candidates drug for treatment of lung cancer. The use of these quinoxaline derivatives in combination with zinc can offer alternative treatment options for lung cancer.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death globally, especially in low and middle-income countries. TB is primarily a curable disease, with chemotherapy predicated on a combination of four drugs. The increase in multiple forms of drug-resistant TB is a major cause for concern, underpinning the importance of a continuous pipeline of new anti-TB agents. Drug repositioning - that is, the optimization of existing drugs for new therapeutic indications - has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, has modest in vitro antimycobacterial activity. Through a multi-disciplinary approach combining aspects of chemistry and biology, this study investigated the pharmacological and physicochemical properties of FA that might be exploited for optimization of FA as a lead compound for TB drug discovery. FA is a weak carboxylic acid, and it was hypothesised that the carboxylic acid moiety limits its permeation of the complex mycobacterial cell wall. Therefore, this study aimed to identify novel FA analogues with improved permeation properties and designed to act as potential prodrugs. By modifying the C-3 hydroxyl and the carboxylic acid moiety, alkyl and aminoquinoline derivatives were covalently fused to FA through ester and amide coupling reactions to generate hybrids and/or potential prodrugs.