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: IH220100017
Funder
Australian Research Council
Funding Amount
$4,808,669.00
Summary
ARC Research Hub for Advanced Manufacture of Targeted Radiopharmaceuticals. Radiopharmaceuticals are emerging as next generation medical technologies for addressing complex health challenges, and their manufacture offers significant economic benefit to Australia. The ARC Research Hub for Advanced Manufacture of Targeted Radiopharmaceuticals (AMTAR) aims to establish a manufacturing platform for new medical technologies combining innovations in biotechnology and pharmaceutical science. The progra ....ARC Research Hub for Advanced Manufacture of Targeted Radiopharmaceuticals. Radiopharmaceuticals are emerging as next generation medical technologies for addressing complex health challenges, and their manufacture offers significant economic benefit to Australia. The ARC Research Hub for Advanced Manufacture of Targeted Radiopharmaceuticals (AMTAR) aims to establish a manufacturing platform for new medical technologies combining innovations in biotechnology and pharmaceutical science. The program addresses industry-led challenges for translation of biologics as molecular radiopharmaceuticals, building capacity in biomanufacturing, radiobiology and radiochemistry. The program establishes a dedicated manufacturing pipeline, future-proofing production and securing supply chain of next generation medical technologies.Read moreRead less
Industrial Transformation Training Centres - Grant ID: IC180100021
Funder
Australian Research Council
Funding Amount
$4,163,359.00
Summary
ARC Training Centre for the Development of Tools for Fragment Based Design. The ARC Training Centre for the Development of Tools for Fragment Based Design aims to inspire the next generation of drug discovery research leaders. It plans to provide direct experience with industry partners, training and master classes in early stage drug-discovery from industry experts. The Centre is expected to accelerate research translation and industry engagement by providing an efficient strategy for the scree ....ARC Training Centre for the Development of Tools for Fragment Based Design. The ARC Training Centre for the Development of Tools for Fragment Based Design aims to inspire the next generation of drug discovery research leaders. It plans to provide direct experience with industry partners, training and master classes in early stage drug-discovery from industry experts. The Centre is expected to accelerate research translation and industry engagement by providing an efficient strategy for the screening of a biological target and early medicinal chemistry for optimisation. The expected outcome of the Centre is to equip the trainees with the skills to make key contributions to the sustainability and growth of the sector and to provide significant capacity to address global challenges for 21st century pharmaceutical innovation.Read moreRead less
The Intended and Unintended Impact of Policy for Adaptive Policy Management. The project aims to advance knowledge about the intended and unintended consequences of policy on health and well-being. It expects to innovate through new methods and novel data to integrate policy evaluation into the policy cycle in a timely fashion to prevent harm from occurring. It also leverages technology to track policy effects in real time. Expected outcomes of this project include new knowledge and enhanced pol ....The Intended and Unintended Impact of Policy for Adaptive Policy Management. The project aims to advance knowledge about the intended and unintended consequences of policy on health and well-being. It expects to innovate through new methods and novel data to integrate policy evaluation into the policy cycle in a timely fashion to prevent harm from occurring. It also leverages technology to track policy effects in real time. Expected outcomes of this project include new knowledge and enhanced policy infrastructure using new methods and interdisciplinary approaches. Significant benefits include improvements to: (1) policy management by government departments; (2) the health and wellbeing of the Australians they serve; (3) our Partners' capacity to consult governments on how technology can assist policy management. Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE130100203
Funder
Australian Research Council
Funding Amount
$385,000.00
Summary
Autonomous benthic observing system. This project seeks to improve our ability to monitor marine habitats and characterise their variability by enhancing the Integrated Marine Observing system (IMOS) Autonomous Underwater Vehicle (AUV) Facility. The new AUV infrastructure will reduce operating costs, increase robustness of the sampling effort and insure continued operation for the next decade.
ARC Centre of Excellence for Children and Families over the Life Course. New solutions are needed to underpin the Australian social ideal of a fair go, and to drive future global economic productivity. The Australian Productivity Commission identifies deep and persistent disadvantage as a significant problem in Australia given the failure of growing national prosperity over the past two decades to benefit underprivileged Australians. Social disadvantage is a global challenge. This Centre will ad ....ARC Centre of Excellence for Children and Families over the Life Course. New solutions are needed to underpin the Australian social ideal of a fair go, and to drive future global economic productivity. The Australian Productivity Commission identifies deep and persistent disadvantage as a significant problem in Australia given the failure of growing national prosperity over the past two decades to benefit underprivileged Australians. Social disadvantage is a global challenge. This Centre will advance basic, applied and translational research to reduce intergenerational and long-term disadvantage. Through the maturation of longitudinal datasets and advanced data integration we can follow the journeys of Australian families over generations and across the life course. This data will provide evidence for new policies and make a real difference to the lives of children and families.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100219
Funder
Australian Research Council
Funding Amount
$170,000.00
Summary
A multi-institutional environmental radioactivity research centre. This project aims to establish an environmental radioactivity research centre, equipped with ultra-low background and high-resolution alpha and gamma spectrometry systems, radon detectors and radium delayed coincidence counters. The centre will address a critical demand in Australia for precise analysis of a large suite of natural and artificial radionuclides, which will be used as tracers and chronological tools to investigate k ....A multi-institutional environmental radioactivity research centre. This project aims to establish an environmental radioactivity research centre, equipped with ultra-low background and high-resolution alpha and gamma spectrometry systems, radon detectors and radium delayed coincidence counters. The centre will address a critical demand in Australia for precise analysis of a large suite of natural and artificial radionuclides, which will be used as tracers and chronological tools to investigate key questions in oceanography and the mining and energy, archaeological, agricultural, and forestry sectors. The facility is expected to substantially increase expertise and training in radionuclides in Australia, and promote high-level research collaborations and outputs of both national and international significance. Major outcomes of the proposed facility include better understanding of how oceans regulate climate and improved capacity to assess effects of radiation on natural ecosystems.Read moreRead less
Modern human origins and early behavioural complexity in Australia and Southeast Asia. This project tackles a fundamental issue in world prehistory: how and when did humans first cross from Southeast Asia into Australia. Three new archaeological excavations using novel methods of analysis will assess the nature of behavioural complexity and human evolution at the time when Australia was first colonised over 45,000 years ago.