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.
Design of Cost-effective Compositionally Complex Alloys. This project aims to develop low-cost and corrosion resistant compositionally complex alloys and associated processes to concurrently achieve high strength and high toughness using an innovative design strategy. The project expects to overcome the major limitations of this new type of alloys, enabling their practical applications in industry, creating new knowledge of materials science. Expected outcomes include commercialisation ready ne ....Design of Cost-effective Compositionally Complex Alloys. This project aims to develop low-cost and corrosion resistant compositionally complex alloys and associated processes to concurrently achieve high strength and high toughness using an innovative design strategy. The project expects to overcome the major limitations of this new type of alloys, enabling their practical applications in industry, creating new knowledge of materials science. Expected outcomes include commercialisation ready new alloys, breakthrough fundamental understanding of the mechanisms and long-term institutional collaboration. This should provide significant benefits, such as enhancement of Australia’s capacity of alloy development and manufacturing and strengthening the country’s world leading position in this area.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100156
Funder
Australian Research Council
Funding Amount
$250,000.00
Summary
Advanced Laser Additive Manufacturing System for Extended Applications to Surface Engineering, Direct Manufacturing and New Alloy Development. Advanced laser additive manufacturing system for extended applications to surface engineering, direct manufacturing and new alloy development: This project will provide an advanced laser additive manufacturing system for extended applications. Although the facility was originally designed for forefront additive manufacturing, it enables innovative resear ....Advanced Laser Additive Manufacturing System for Extended Applications to Surface Engineering, Direct Manufacturing and New Alloy Development. Advanced laser additive manufacturing system for extended applications to surface engineering, direct manufacturing and new alloy development: This project will provide an advanced laser additive manufacturing system for extended applications. Although the facility was originally designed for forefront additive manufacturing, it enables innovative research on surface engineering to solve the long standing corrosion and wear problems associated with metal components and to produce biomedical coatings on titanium implants. The facility can also be used to develop high quality alloys, including titanium and magnesium alloys, through an accelerated metallurgy approach, leading to breakthrough progress in metal research. Such alloys are highly desired by automotive and aerospace industries to improve fuel efficiency through weight reduction. Read moreRead less
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
Optimal transitional surface for a new continuous press forming process. This project addresses the National Research Priority - Frontier Technologies for Building and Transforming Australian Industries through smart information use. This project aims to gain fundamental scientific understanding of a manufacturing process with the aim of developing a tool that will enhance existing manufacturing processes and controls from an 'art of expertise' to a scientific understanding and improvement. Th ....Optimal transitional surface for a new continuous press forming process. This project addresses the National Research Priority - Frontier Technologies for Building and Transforming Australian Industries through smart information use. This project aims to gain fundamental scientific understanding of a manufacturing process with the aim of developing a tool that will enhance existing manufacturing processes and controls from an 'art of expertise' to a scientific understanding and improvement. This manufacturing area represents a niche market for Australian manufacturing and the development of a product that enhances productivity and reduces costs has the potential to elevate Australian manufacturers in the export market and create economic benefit for Australia.Read moreRead less
ARC Centre of Excellence - Design in Light Metals. Under the national Light Metals Action Agenda, Australia recognizes a strategic interest in the production, processing and applications of the light metals, and a growth in global markets for light metals technology. Light metals research is a designated national priority, and this Centre will provide the national focus in strategic fundamental research, the critical level of investment and the level of innovation necessary to achieve competiti ....ARC Centre of Excellence - Design in Light Metals. Under the national Light Metals Action Agenda, Australia recognizes a strategic interest in the production, processing and applications of the light metals, and a growth in global markets for light metals technology. Light metals research is a designated national priority, and this Centre will provide the national focus in strategic fundamental research, the critical level of investment and the level of innovation necessary to achieve competitive advantage from an outstanding research base. As a major contributor to a strategic network of national research capabilities, it will underpin substantial developments in the light metals industry nationally and globally, and extend linkages with major research centres internationally.Read moreRead less
High performance ultrasonically processed biodegradable alloy products. This project aims to develop new alloy processing technology to improve the material properties of biodegradable products such as plates, microclips and wound-closing devices. The project aims to understand and model the role of external fields such as ultrasonic treatment in the development of microstructure, including grain nucleation and formation processes, in biodegradable magnesium alloy components. The project plans t ....High performance ultrasonically processed biodegradable alloy products. This project aims to develop new alloy processing technology to improve the material properties of biodegradable products such as plates, microclips and wound-closing devices. The project aims to understand and model the role of external fields such as ultrasonic treatment in the development of microstructure, including grain nucleation and formation processes, in biodegradable magnesium alloy components. The project plans to fabricate and evaluate the performance of medical devices incorporating ultrasonically processed alloy products. Project outcomes are intended to be used to optimise the application of external fields for property and processing improvement.Read moreRead less
New Synthetic Routes to the Immobilisation of Mixed Valence Transition Metal Complexes on Conducting Metal Oxides. Highly coloured, electrochemically active transition metal dyes may find application electrochromic devices, where they may switch between contrasting coloured forms through a simple redox reaction. A prerequisite is that the dye be immobilised onto a solid conducting support whilst preserving the electrochemical and optical properties of the dye found in solution. This project tack ....New Synthetic Routes to the Immobilisation of Mixed Valence Transition Metal Complexes on Conducting Metal Oxides. Highly coloured, electrochemically active transition metal dyes may find application electrochromic devices, where they may switch between contrasting coloured forms through a simple redox reaction. A prerequisite is that the dye be immobilised onto a solid conducting support whilst preserving the electrochemical and optical properties of the dye found in solution. This project tackles this problem through a combination of organic and inorganic synthesis to develop new electrochromic dyes that may be attached to mesoporous titania.Read moreRead less