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.
New Lead-Free Brass Solutions for Drinking Water Applications. The aim of this Linkage Project is to provide viable material solutions to address the health problem of Lead-contamination in drinking water arising from Leaded-brass plumbing products and the impact Lead-removal from brass will have on the brass industry. In order to achieve this, this project engages leading multidisciplinary researchers along with Australian and international industry partners from across the brass industry suppl ....New Lead-Free Brass Solutions for Drinking Water Applications. The aim of this Linkage Project is to provide viable material solutions to address the health problem of Lead-contamination in drinking water arising from Leaded-brass plumbing products and the impact Lead-removal from brass will have on the brass industry. In order to achieve this, this project engages leading multidisciplinary researchers along with Australian and international industry partners from across the brass industry supply and sales network. This project seeks to identify and harness the key material-product attributes required to develop and implement new, lead-free alloy alternatives that meet health-compliance, production and commercial viability, that offer benefits across the industry network and health benefits to society.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100003
Funder
Australian Research Council
Funding Amount
$280,000.00
Summary
Flexible forming facility for low cost light weight applications. Flexible forming facility for low-cost light-weight applications: This project will establish Australia’s first flexible roll forming facility. The facility will be unique in the world, being specifically designed to roll form the most advanced high strength alloys into complex three-dimensional shapes and investigate their material behaviour under a wide range of loading conditions. This technology represents a step change in com ....Flexible forming facility for low cost light weight applications. Flexible forming facility for low-cost light-weight applications: This project will establish Australia’s first flexible roll forming facility. The facility will be unique in the world, being specifically designed to roll form the most advanced high strength alloys into complex three-dimensional shapes and investigate their material behaviour under a wide range of loading conditions. This technology represents a step change in commercial processing and has the capacity to form materials with high strength and limited ductility. This will lead to the development of new techniques for the manufacture of new advanced materials including advanced high strength steels, composites, nano structured metals and light metal alloys for automotive and aerospace applications.Read moreRead less
ARC Centre of Excellence - in Ore Deposits. Australia's minerals industry faces a two-fold challenge - to find new ore deposits and to mine them with maximum efficiency and minimal environmental impact. Those challenges demand a new generation of focused ore deposit research, tailored specifically for the Australian context. The Centre of Excellence in Ore Deposits will provide the foundation of fundamental research required by a successful, efficient and sustainable Australian minerals industry ....ARC Centre of Excellence - in Ore Deposits. Australia's minerals industry faces a two-fold challenge - to find new ore deposits and to mine them with maximum efficiency and minimal environmental impact. Those challenges demand a new generation of focused ore deposit research, tailored specifically for the Australian context. The Centre of Excellence in Ore Deposits will provide the foundation of fundamental research required by a successful, efficient and sustainable Australian minerals industry. The Centre will also play a leading role in the undergraduate and postgraduate training of future geoscientists. The concentration of internationally recognised researchers in the Centre will ensure it maintains its premier position in the international ore deposit research arena.Read moreRead less
Industrial Transformation Training Centres - Grant ID: IC180100005
Funder
Australian Research Council
Funding Amount
$4,889,410.00
Summary
ARC Training Centre in Surface Engineering for Advanced Materials. The ARC Training Centre in Surface Engineering for Advanced Materials aims to provide pathways for job creation and a high quality workforce in manufacturing. Surface engineering for advanced materials is a core need in all manufacturing sectors and controls the efficiency, productivity and sustainability of Australian industry. This Centre will integrate industry-university cooperation for applied training within an industrial s ....ARC Training Centre in Surface Engineering for Advanced Materials. The ARC Training Centre in Surface Engineering for Advanced Materials aims to provide pathways for job creation and a high quality workforce in manufacturing. Surface engineering for advanced materials is a core need in all manufacturing sectors and controls the efficiency, productivity and sustainability of Australian industry. This Centre will integrate industry-university cooperation for applied training within an industrial setting and will cover a spectrum of applications ranging from thin films to thick coatings and additive layered materials. The Centre will pursue outcomes that are reflected in terms of industry-fit researchers and deliver commercial benefits for industry.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0346515
Funder
Australian Research Council
Funding Amount
$507,000.00
Summary
Fluorescence Detector for the Australian National Beamline Facility. X-ray absorption spectroscopy (XAS) is an extremely important synchrotron radiation tool for determining the local structure around an X-ray absorbing atom. This has many applications in the study of materials, minerals, metal complexes, and metalloproteins and can often be used to obtain information that is not available by other techniques, because structural information can be obtained in the solid or solution state and in ....Fluorescence Detector for the Australian National Beamline Facility. X-ray absorption spectroscopy (XAS) is an extremely important synchrotron radiation tool for determining the local structure around an X-ray absorbing atom. This has many applications in the study of materials, minerals, metal complexes, and metalloproteins and can often be used to obtain information that is not available by other techniques, because structural information can be obtained in the solid or solution state and in mixtures. The current proposal is aimed at introducing new technology into the Australian National Beamline Facility that will greatly improve the quality and quantity of experiments that can be performed and extend studies into dilute solutions and protein samples.Read moreRead less
Experimental and empirical insight into melting of the early Earth's mantle. The early Earth's mantle produced melt at much higher temperature than today, creating rocks with unique chemistries and mineralogies. But pressing knowledge gaps about hot mantle melting remain. The aim of this project is to generate new experimental and empirical knowledge to help closing these gaps by:
(i) conducting high pressure experiments to refine phase-composition relationships and element partitioning;
(ii) qu ....Experimental and empirical insight into melting of the early Earth's mantle. The early Earth's mantle produced melt at much higher temperature than today, creating rocks with unique chemistries and mineralogies. But pressing knowledge gaps about hot mantle melting remain. The aim of this project is to generate new experimental and empirical knowledge to help closing these gaps by:
(i) conducting high pressure experiments to refine phase-composition relationships and element partitioning;
(ii) quantifying mineral fabrics in cratonic peridotites to understand the movement of early continents; and
(iii) constructing the first petrological deep time model for greenstone belt volcanic rocks.
The expected outcomes are better models for the early Earth's melting and tectonic regimes and insight into the emergence of land.Read moreRead less
Industrial Transformation Training Centres - Grant ID: IC160100036
Funder
Australian Research Council
Funding Amount
$4,881,754.00
Summary
ARC Training Centre in Alloy Innovation for Mining Efficiency. ARC Training Centre in Alloy Innovation for Mining Efficiency. This centre aims to make Australian manufacturers dominant in the multi-billion dollar mining equipment sector by training innovators to design the world’s best highly customized long-life, wear resistant components. It intends to rapidly develop customized alloys that excel in severe mining conditions, using three-dimensional printing, novel characterisation and its netw ....ARC Training Centre in Alloy Innovation for Mining Efficiency. ARC Training Centre in Alloy Innovation for Mining Efficiency. This centre aims to make Australian manufacturers dominant in the multi-billion dollar mining equipment sector by training innovators to design the world’s best highly customized long-life, wear resistant components. It intends to rapidly develop customized alloys that excel in severe mining conditions, using three-dimensional printing, novel characterisation and its networked training environment. It expects these innovations will enable much needed efficiencies after the end of the mining super-cycle. Anticipated outcomes are the design of products with superior alloy design and material selection; jobs growth and security in the mining component production sector; and increased mining efficiency and cost reduction.Read moreRead less
High performance cast magnesium alloys. Reducing the weight of cars, particularly their engines, enables substantial reductions in fuel consumption and greenhouse gas emissions. A new generation of magnesium alloys will be developed by this project for the manufacture of considerably lighter components with improved mechanical performance for powertrain and structural applications.