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.
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.
What makes for successful numeracy education in remote Indigenous contexts: an ethnographic case study approach. There are many successful teachers and schools who have enabled remote Indigenous learners to engage with, and learn, school mathematics. But what do they do? How do they do it? This project investigates and documents successful practices in 32 schools located in remote communities. The project includes the many aspects of teaching practice.
Social and geographical location and its impact on mathematics teaching and learning. Too many students from poor urban backgrounds or from rural communities are at risk of underperforming in school mathematics. This project identifies the critical factors that contribute to this failure and seeks to develop improved practices to enable greater access to school mathematics.
Developmental engineering education in the primary school. Primary school students will learn about engineers and how engineering shapes our society. Students will develop important design processes in solving authentic, engineering-based problems. Their learning in the increasingly important science, technology, engineering, and mathematics (STEM) area will be enhanced, providing a foundation for addressing the increasing skills shortage in engineering.
Bringing back Australia's lost woodland biodiversity: towards strategic multi-species reintroductions. Australia has the highest rate of mammal extinction of any continent on the planet. This has reduced biodiversity and compromised many important ecological processes. What is the best way to re-build depauperate mammal communities with multi-species reintroductions? What effects do multi-species reintroductions have on recipient ecosystems? This project aims to explore these questions by reintr ....Bringing back Australia's lost woodland biodiversity: towards strategic multi-species reintroductions. Australia has the highest rate of mammal extinction of any continent on the planet. This has reduced biodiversity and compromised many important ecological processes. What is the best way to re-build depauperate mammal communities with multi-species reintroductions? What effects do multi-species reintroductions have on recipient ecosystems? This project aims to explore these questions by reintroducing three mammal species to a critically endangered temperate woodland: a carnivore (the eastern quoll), an insectivore (yellow-footed antechinus), and a herbivore (the eastern chestnut mouse). Results from this sequenced multi-species reintroduction experiment will have broad applicability to ecosystem restoration in Australia and overseas.Read moreRead less
Have we already lost the Australian lungfish? This project aims to use radiocarbon ageing, conservation genetics and modelling to identify threats to the long-term survival of the Australian lungfish, the world's oldest living vertebrate. This project will provide managers with a powerful tool to prioritise management interventions to ensure the conservation of the species and to pull it back from extinction.
Reintroduction of ecosystem engineers as a woodland restoration tool. Can we help restore woodlands by reintroducing extinct native mammals? Through a strategic partnership combining innovative research and conservation action, this project will investigate how returning extinct 'ecosystem engineers' could be used as a tool for restoring healthy temperate woodland ecosystems.