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.
Data-driven monitoring of raceway dynamics in ironmaking blast furnaces. Raceway dynamics in ironmaking blast furnaces affect operational stability and cost considerably, yet their dynamic behaviour has not been well monitored online. The project aims to develop a data-driven model for monitoring the internal state of gas-solid-powder reacting flow in the raceway and predicting raceway anomalies online. It will be achieved by combining particle-fluid numerical simulations with data processing an ....Data-driven monitoring of raceway dynamics in ironmaking blast furnaces. Raceway dynamics in ironmaking blast furnaces affect operational stability and cost considerably, yet their dynamic behaviour has not been well monitored online. The project aims to develop a data-driven model for monitoring the internal state of gas-solid-powder reacting flow in the raceway and predicting raceway anomalies online. It will be achieved by combining particle-fluid numerical simulations with data processing and reduced-order state observer, supported by lab/plant experiments, and collaborating with two industry partners from coal and steel industries. The project outcomes including codes, models and raceway control strategies can help promote Australian metallurgical coal's global markets and ultimately the Australian economy.Read moreRead less
ARC Centre of Excellence for Enabling Eco-Efficient Beneficiation of Minerals. The aim of the Centre is to progress scientific knowledge to establish transformational improvement in minerals beneficiation, essential for meeting global demand for metals. The research aims to achieve more selective, faster, and efficient separations, combining major advances in separation technologies with increased functionality of new reagents. The Centre outcomes will also ensure the sustainability of the miner ....ARC Centre of Excellence for Enabling Eco-Efficient Beneficiation of Minerals. The aim of the Centre is to progress scientific knowledge to establish transformational improvement in minerals beneficiation, essential for meeting global demand for metals. The research aims to achieve more selective, faster, and efficient separations, combining major advances in separation technologies with increased functionality of new reagents. The Centre outcomes will also ensure the sustainability of the minerals industry in Australia, through a significant reduction in cost, environmental impact, and through lower energy and water usage. The Centre also seeks to establish a new generation of scientists and research leaders in minerals beneficiation to support the innovation needed into the future by this major Australian industry.Read moreRead less
Industrial Transformation Research Hubs - Grant ID: IH130200033
Funder
Australian Research Council
Funding Amount
$2,526,617.00
Summary
ARC Research Hub for Australian Copper-Uranium. ARC Research Hub for Australian Copper-Uranium. This Research Hub aims to develop, test and commercialise new, safe and cost-effective methods to separate radionuclides from copper concentrates derived from copper/uranium ores. The Research Hub will focus on harnessing the expertise and facilities of Australia's key 'resource' companies and universities to enable Australia to position itself as a world leader in copper production and associated tec ....ARC Research Hub for Australian Copper-Uranium. ARC Research Hub for Australian Copper-Uranium. This Research Hub aims to develop, test and commercialise new, safe and cost-effective methods to separate radionuclides from copper concentrates derived from copper/uranium ores. The Research Hub will focus on harnessing the expertise and facilities of Australia's key 'resource' companies and universities to enable Australia to position itself as a world leader in copper production and associated technology.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100112
Funder
Australian Research Council
Funding Amount
$275,000.00
Summary
A Raman facility for advanced research supporting Australia’s natural gas, oil, coal and minerals industries. This modern Raman Spectroscopy facility will support the science and engineering that underpins the production and processing of Australia’s natural resources. Using high-pressure fibre optics, novel lasers and advanced imaging, the facility will enable the monitoring and improvement of processes and materials under extreme conditions.