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
Development of a topical treatment to replace surgical mulesing in sheep. 10,800 farms in Australia are sheep farms and a further 30,000 have sheep. Exports of wool earn over $2 billion annually. The animal rights campaign to ban mulesing has forced the industry to outlaw mulesing by 2010. Mulesing is largely confined to Australian Merino sheep and requires Australian research. If practical alternatives are not found costs will rise compromising the economic viability of many sheep farms. C ....Development of a topical treatment to replace surgical mulesing in sheep. 10,800 farms in Australia are sheep farms and a further 30,000 have sheep. Exports of wool earn over $2 billion annually. The animal rights campaign to ban mulesing has forced the industry to outlaw mulesing by 2010. Mulesing is largely confined to Australian Merino sheep and requires Australian research. If practical alternatives are not found costs will rise compromising the economic viability of many sheep farms. Chemical use on the breech will increase causing environmental contamination. A simple topical alternative to mulesing will allow farmers to economically manage flies and satisfy welfare imperatives. This will support rural communities and sustain Australia's export income from wool.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.
Discovery And Development Of Better Pain Treatments
Funder
National Health and Medical Research Council
Funding Amount
$9,613,850.00
Summary
Many forms of pain remain poorly treated, leading to significant quality of life and economic losses. This Program grant will discover and characterise new peptides from cone snails and spiders that modulate specific channels in nerves that are critical to the transmission of pain signals to the brain. Using advanced chemical and structural approaches, promising leads will be optimised for potency and stability and evaluated in disease and pathway-specific models of pain to establish their clini ....Many forms of pain remain poorly treated, leading to significant quality of life and economic losses. This Program grant will discover and characterise new peptides from cone snails and spiders that modulate specific channels in nerves that are critical to the transmission of pain signals to the brain. Using advanced chemical and structural approaches, promising leads will be optimised for potency and stability and evaluated in disease and pathway-specific models of pain to establish their clinical potential.Read moreRead less
Prevention and treatment of chlamydiosis and cryptococcosis in koalas. This project aims to generate increased understanding of the aetiology and pathogenesis of the two most prevalent and debilitating infectious diseases of koalas to make improved decisions regarding therapeutic intervention, prevention and management. Chlamydiosis, caused by two chlamydial bacteria, affects koala fertility, urinary tract function and eyesight. Cryptococcosis, caused by the fungus Cryptococcus gattii, may resul ....Prevention and treatment of chlamydiosis and cryptococcosis in koalas. This project aims to generate increased understanding of the aetiology and pathogenesis of the two most prevalent and debilitating infectious diseases of koalas to make improved decisions regarding therapeutic intervention, prevention and management. Chlamydiosis, caused by two chlamydial bacteria, affects koala fertility, urinary tract function and eyesight. Cryptococcosis, caused by the fungus Cryptococcus gattii, may result in koala morbidity and death. Planned therapeutic trials, prevention strategies and the development of optimal husbandry strategies will provide knowledge that will lead to reduced koala morbidity through improved understanding of the interactions amongst infectious pathogens, the animal host and the environment.Read moreRead less
Establishment of Therapeutically Relevant Animal Models and Markers for Crohn's Disease. Crohn's disease is a devastating life long disease, affecting 0.5% of the world population. There is urgent economic and social need to develop new and better drugs to treat the symptoms and underlying cause of this debilitating disease. Social benefits include the improved quality of life of sufferers that positively impacts society. Economic benefit includes income derived from commercialisation of rese ....Establishment of Therapeutically Relevant Animal Models and Markers for Crohn's Disease. Crohn's disease is a devastating life long disease, affecting 0.5% of the world population. There is urgent economic and social need to develop new and better drugs to treat the symptoms and underlying cause of this debilitating disease. Social benefits include the improved quality of life of sufferers that positively impacts society. Economic benefit includes income derived from commercialisation of research outcomes and the contribution this project makes to high value employment in the biotechnology sector.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0668246
Funder
Australian Research Council
Funding Amount
$400,000.00
Summary
Advanced Cell Labelling and Imaging Facility. Understanding the genetic regulation of cellular processes such as migration, differentiation and growth is an important frontier technology with significant biomedical potential. The Australian community is facing an increasing need to provide solutions for a variety of human diseases and disorders, including birth defects, nervous system injury and stroke, and ageing-related conditions. The proposed facility will allow researchers to test in vivo g ....Advanced Cell Labelling and Imaging Facility. Understanding the genetic regulation of cellular processes such as migration, differentiation and growth is an important frontier technology with significant biomedical potential. The Australian community is facing an increasing need to provide solutions for a variety of human diseases and disorders, including birth defects, nervous system injury and stroke, and ageing-related conditions. The proposed facility will allow researchers to test in vivo gene/pharmaceutical therapies as well as to better understand the genetic regulation of normal cellular processes. Read moreRead less
Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a gr ....Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a greater understanding of how the nervous system functions. This knowledge will help in the design of new drugs to treat a variety of diseases and disorders. Essentially we will use a chemical armoury developed by the cone snail to design state-of-the-art mini-protein drugs.Read moreRead less