Examination Of The Molecular Pharmacology Of Anthracyclines Induced Via Their Interaction With Iron
Funder
National Health and Medical Research Council
Funding Amount
$618,401.00
Summary
Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and ....Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and haem synthesis. Hence, this effect probably contributes to the cytotoxic activity of anthracyclines on the heart. We showed that novel drugs developed in my lab that bind Fe called chelators show high activity in animals (DR4) and prevent anthracycline-mediated Fe accumulation in ferritin. Importantly, Fe chelators have been shown to inhibit anthracycline-mediated cardiotoxicity. Indeed, the clinically used cardioprotective agent, ICRF-187, is actually an Fe chelator (5, DR6). However, ICRF-187 is not totally successful in terms of its cardioprotective effects and can cause myelosuppression (5, DR6). While the clinically used chelator, desferrioxamine (DFO), can prevent anthracycline-mediated cardiotoxicity, its poor membrane permeability limits its effectiveness. Our chelators are highly permeable and overcome the disadvantages of DFO (DR4). Thus, they are vital to examine for preventing anthracycline-mediated cardiotoxicity. In this proposal we will examine the changes in Fe metabolism induced by anthracyclines and test the hypothesis that novel Fe chelators may prevent the cardiotoxicity of these agents. We also aim to be the first to assess if preparation of anthracyclines which cannot bind iron prevents their cardiotoxicity. This will be done by preparing metal complexes of these drugs which prevent Fe-binding eg. anthracycline-zinc complexes. These studies are important for the development of less cardiotoxic forms of these very useful anti-tumour agents.Read moreRead less
Pharmacology Of Potential Anti-Tumour Agents: Iron Chelators Of The BpT Class
Funder
National Health and Medical Research Council
Funding Amount
$585,455.00
Summary
Pharmacology of Potential Anti-Tumour Agents: Iron Chelators of the BpT Class Cancer cells have a high iron requirement for DNA synthesis and many clinical trials showed Fe chelators are effective anti-cancer drugs. Their potential to act as anti-tumour agents has been confirmed by the entrance of Triapine into widespread NCI clinical trials. In this NHMRC Renewal, we will perform pharmacological and preclinical studies to promote the development of BpT chelators as novel anti-tumour agents.
Mechanisms Of Glucocorticoid Resistance In Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Glucocorticoids are extremely active drugs used in the treatment of childhood acute lymphoblastic leukaemia (ALL), yet a proportion of patients respond poorly to therapy and exhibit resistance at relapse. Clinically relevant mechanisms of glucocorticoid resistance are poorly understood, principally due to lack of appropriate experimental models. This project will reveal novel mechanisms of drug resistance in childhood leukaemia and lead to novel therapeutic strategies to improve outcome.
Improving Treatment Strategies For Chronic Alphaviral Arthritic Diseases
Funder
National Health and Medical Research Council
Funding Amount
$643,624.00
Summary
Chikungunya virus and Ross River virus cause epidemics of acute and chronic arthritic disease in humans, which is often poorly managed with current treatments. This grant seeks to understand the mechanisms that give rise to disease in order to identify improved treatment strategies. Both the persistence of viral replication in joint tissues and unnecessary inflammatory responses appear to be important factors driving chronic disease.
Applying behavioural insights to the tax system in Australia. Applying behavioural insights to the tax system in Australia. This project aims to improve compliance and payment in the Australian tax system. It aims to tackle debts of individuals and businesses, the most challenging aspect of tax systems, by applying behavioural insights to design innovative payment interventions and conducting rigorous randomised controlled trials to evaluate their effects. An empirical analysis will account for ....Applying behavioural insights to the tax system in Australia. Applying behavioural insights to the tax system in Australia. This project aims to improve compliance and payment in the Australian tax system. It aims to tackle debts of individuals and businesses, the most challenging aspect of tax systems, by applying behavioural insights to design innovative payment interventions and conducting rigorous randomised controlled trials to evaluate their effects. An empirical analysis will account for heterogeneity in treatment responses, and the findings will be combined with a study of regulatory and administrative processes to support the ultimate goal of a legitimate, fair, cost-effective and responsive tax system.Read moreRead less
Driving Change: Using Emergency Department Data To Reduce Alcohol-related Harm
Funder
National Health and Medical Research Council
Funding Amount
$1,468,026.00
Summary
The proposed project is a system change within partner emergency departments, providing them the information and tools to act on both risky alcohol consumption in individual patients and the sources of alcohol in the community which cause the harm they experience. Most importantly, the proposed public health interventions act as a tool for emergency departments to regularly raise awareness with the public and policymakers regarding the impact of alcohol on patients, clinicians and hospitals.
Back to the Future: Interglacial Warming and the West Antarctic Ice Sheet . The Antarctic is highly-sensitive to abrupt changes caused by the passing of tipping points within the climate system. Crucially, the instrumental record is too short to resolve major uncertainties surrounding future warming. The Last Interglacial (125,000 yrs ago) was 2°C warmer than today and experienced 6-11 m higher global sea levels. The role of Antarctica is vital for constraining sea-level projections. This Austra ....Back to the Future: Interglacial Warming and the West Antarctic Ice Sheet . The Antarctic is highly-sensitive to abrupt changes caused by the passing of tipping points within the climate system. Crucially, the instrumental record is too short to resolve major uncertainties surrounding future warming. The Last Interglacial (125,000 yrs ago) was 2°C warmer than today and experienced 6-11 m higher global sea levels. The role of Antarctica is vital for constraining sea-level projections. This Australian-led international project aims to determine the mechanisms and impacts of past interglacial Antarctic warming up to 2°C (relative to pre-industrial). Innovative techniques integrating horizontal ice cores and high resolution marine records will help identify polar tipping points and better plan for impacts in Australia.Read moreRead less
Risks of rapid ocean warming at the Antarctic continental margin. This project aims to comprehensively understand the interconnected processes by which oceanic heat is circulated towards Antarctica. The risk of rapid ocean warming at the Antarctic margin is profound, with change already detected via deep ocean warming, land-ice melt, and ice shelf collapse. Yet this region remains poorly understood, with only limited observations due to both a harsh environment and a lack of standard data stream ....Risks of rapid ocean warming at the Antarctic continental margin. This project aims to comprehensively understand the interconnected processes by which oceanic heat is circulated towards Antarctica. The risk of rapid ocean warming at the Antarctic margin is profound, with change already detected via deep ocean warming, land-ice melt, and ice shelf collapse. Yet this region remains poorly understood, with only limited observations due to both a harsh environment and a lack of standard data streams. This project will use high-resolution global and regional ocean/sea-ice models to examine mechanisms for rapid warming of Antarctic continental shelf waters via both large-scale drivers and fine-scale processes, including mesoscale eddies, tide-topography interactions, and bottom boundary flows. This work will better constrain future rates of ice melt around Antarctica by providing vital knowledge of the ocean processes, dynamics, and feedbacks relating to warm water intrusion onto the Antarctic continental shelf.Read moreRead less
Examining the vulnerability of ocean carbon biogeochemistry in a high CO2 world. Rising CO2 levels in the atmosphere from human activity is changing the biogeochemistry of the ocean, with large potential consequences on future atmospheric CO2. This work will explore these changes and will result in a more complete understanding of how the ocean will either accelerate or delay the increase in atmospheric CO2.
Novel water treatment processes. The objective of this project is the discovery of novel methods for the treatment and reuse of water for both industrial and household applications. Improved treatment systems with the potential for water reuse offer significant improvements to our overall water management potential. The first part of the project is designed to focus on the study of hot bubble column evaporators for solute decomposition, sterilisation and the de-watering of heavily contaminated i ....Novel water treatment processes. The objective of this project is the discovery of novel methods for the treatment and reuse of water for both industrial and household applications. Improved treatment systems with the potential for water reuse offer significant improvements to our overall water management potential. The first part of the project is designed to focus on the study of hot bubble column evaporators for solute decomposition, sterilisation and the de-watering of heavily contaminated industrial wastewater. The second part would be based on the study of a suitable depth filter medium for the treatment of partially treated household sewage water. This is designed to form part of an on-site household sewage water treatment and reuse system which is currently being developed.Read moreRead less