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.
Space gravity: squeezing the last drop of hydrological information out of current and future missions. Australia needs space gravity measurements in order to estimate regional-scale total water storage changes on our continent. This project will deliver the analysis capability required to exploit all the measurements of the current Gravity Recovery and Climate Experiment (GRACE) mission and to place Australia in a state of readiness for the 2017 GRACE Follow On mission.
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.
The vision we rely on every day to read and recognise faces depends upon the health of the central portion of our retina, the macula. Age-related Macular Degeneration (AMD) is the leading cause of blindness in Australia and the western world. Researchers at the Australian National University are collaborating to bring a new test for AMD severity to the market within 3 years. The objective is to provide doctors with a rapid, cost-effective tool to help them manage treatment.
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
Restorative Justice and Responsive Regulation. The objective of this research is through a series of projects to bring the autor's restorative justice and responsive regulatin research programs of the last decade together, to intergrate them. this means to bear a restorative and responsive approach to transforming the entire legal system, not just criminal or regulatory law/administration. hwever, it does also mean reforming criminological theory with regulatory theory and applying restorative ....Restorative Justice and Responsive Regulation. The objective of this research is through a series of projects to bring the autor's restorative justice and responsive regulatin research programs of the last decade together, to intergrate them. this means to bear a restorative and responsive approach to transforming the entire legal system, not just criminal or regulatory law/administration. hwever, it does also mean reforming criminological theory with regulatory theory and applying restorative justice to business regulation, as well as tort, tax, contract and all areas of law.Read moreRead less