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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
Light-responsive nanomaterials as nanomedicines: new approaches to treating macular degeneration, cancer and other critical unmet therapeutic needs. Nanotechnology is enabling new medicines for the treatment of important diseases such as cancer and macular degeneration. This project will investigate novel nanomaterials for the development of new highly effective medicines that can be controlled after administration, leading to reduced side effects and increased convenience for patients.
Micro- and nano-particulate delivery systems for chemical and biological weapons: physical characterisation and risk assessment. Inert solid powder has been used as a carrier for chemical and biologically-active agents to increase their effectiveness in a range of applications such as chemical weapons, pesticides and insecticides. The aim of this research is to determine the influence of the physical characteristics of particulate delivery systems on their ability to deliver potentially toxic s ....Micro- and nano-particulate delivery systems for chemical and biological weapons: physical characterisation and risk assessment. Inert solid powder has been used as a carrier for chemical and biologically-active agents to increase their effectiveness in a range of applications such as chemical weapons, pesticides and insecticides. The aim of this research is to determine the influence of the physical characteristics of particulate delivery systems on their ability to deliver potentially toxic substances to exposed skin and through protective clothing. This data will provide the first step in the design and development of effective protective clothing/products and safety protocols to safeguard the health of Australians involved in the defence of Australia.Read moreRead less
Investigating the functional interaction between vasopressin and angiotensin receptors. Kidney disease resulting from diabetes is a major health issue for Australians, and indigenous Australians in particular. This project aims to enable improved therapies to be developed, as well as better inform doctors regarding the use of potential combinations of existing pharmaceuticals to treat this condition.