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.
Honesty and efficiency in the provision of expert services: doctors and other experts as participants in economic experiments. Experts serve us when we see the doctor, the financial planner or the car mechanic. In all these case the expert can take advantage of his superior knowledge and sell us something we do not need. This research will inform policy makers about the underlying motives of real world experts and allow them to design better institutions.
Financial decision making in late adulthood. The project aims to examine links between cognitive changes and financial decision-making in late adulthood and also to assess the preparedness of the elderly to combat financial risks due to age-related cognitive decline. Further, it intends to examine how age, education, wealth, health, and other environmental factors influence transfer of financial decision-making responsibilities to spouses or others. It is expected that the research will provide ....Financial decision making in late adulthood. The project aims to examine links between cognitive changes and financial decision-making in late adulthood and also to assess the preparedness of the elderly to combat financial risks due to age-related cognitive decline. Further, it intends to examine how age, education, wealth, health, and other environmental factors influence transfer of financial decision-making responsibilities to spouses or others. It is expected that the research will provide a greater understanding of how cognitive functioning and other factors affect older adults’ financial capacity and willingness to delegate decision-making responsibilities. This understanding could be used to inform policy initiatives to protect elderly individuals and their family members from the risk of financial mismanagement.Read moreRead less
The rise of mistrust: Digital platforms and trust in news media. This project aims to investigate how trust and mistrust in news changes audiences’ behaviours as they increasingly access news through digital platforms. Observing the global crisis of trust, the project will undertake a longitudinal analysis of trust and mistrust in news, a four-country experiment that links trust and audience responses, and an in-depth qualitative study that provides specific contexts of these choices. The resear ....The rise of mistrust: Digital platforms and trust in news media. This project aims to investigate how trust and mistrust in news changes audiences’ behaviours as they increasingly access news through digital platforms. Observing the global crisis of trust, the project will undertake a longitudinal analysis of trust and mistrust in news, a four-country experiment that links trust and audience responses, and an in-depth qualitative study that provides specific contexts of these choices. The research will directly benefit policy makers, as it addresses questions of how to better secure trustworthy news content in an age of increasing dominance of digital platforms that algorithmically sort the range of news available to the Australian public.
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