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NADPH Oxidase In Pathological Angiogenesis In Solid Tumours And Retina
Funder
National Health and Medical Research Council
Funding Amount
$581,989.00
Summary
Understanding blood vessel growth has profound clinical implications for many diseases. Blocking vessel growth is a promising strategy for treatment of cancer and eye complications accompanying diabetes, whereas treatments to stimulate new vessel growth will treat ischemic disorders ie. heart attack and stroke. Here we investigate whether targeting an enzyme that grows blood vessels has potential for making drugs to stop tumor growth or eye damage that occurs with diabetes and premature births.
Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in ....Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in tumour burden was observed while there were no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers from serious problems, including that it requires long infusions and does not readily penetrate cells. Further, in some cancer patients, DFO has shown little activity. Considering these results, we have developed a new group of chelators that show far greater activity than DFO at inhibiting cancer cell growth. These studies have been published in high quality journals such as BLOOD (Richardson et al. 1995, 1997, 1999) and form the basis for the current study. In this study we will examine how these iron-binding drugs work to inhibit the growth of cancer cells compared to their normal counterparts. These studies are important for the rational design of even more effective chelators. Recent studies in my lab have shown that our new chelators have far greater activity than a drug currently used to treat leukemia, known as hydroxyurea (HU). Our studies also show that the chelators act by a variety of mechanisms, explaining their greater activity than HU. Furthermore, we have shown that these chelators show significant anti-tumour activity in mice. The potential of this form of therapy has been confirmed by the entrance of the chelator, Triapine, into clinical trials (Vion Pharmaceuticals, USA). Our chelators are more effective than Triapine, thus, the present project is crucial for developing novel anti-tumour therapies.Read moreRead less
Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
Development Of Novel Anti-epileptic Drugs Targeting Vesicular Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$202,950.00
Summary
Our team developed a drug program targeting a novel mechanism for epilepsy treatment, neuronal synaptic vesicle endocytosis. This project will develop the most promising series of drugs. Preclinical development is advanced, lacking only efficacy data across models predictive of the spectrum of human epilepsies to enable candidate selection for clinical trials. The program will advance a totally new concept for the treatment of epilepsy.
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune diseases. An agent that could block the effects of C5a could be very useful clinically. There is no such drug available as yet. We have developed powerful agents which specifically block C5a in laboratory tests on isolated cells and tissues, and now propose to test their effectiveness in rats in which the above human disease conditions are mimicked. Our preliminary results are very promising, and we will conduct further testing to determine the scope of the actions of the new drugs. One of our new agents is orally active in rats, and we will determine how the blood levels of the drug relate to its beneficial effects. We are also planning to develop agents that are more effective when given by mouth. The results could lead to a new type of anti-inflammatory drug for humans suffering from a variety of diseases that are poorly treatable at present.Read moreRead less
Targeted Cancer Chemotherapy: The Potential Of L-Nucleoside Prodrugs
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
The aim of this project to develop novel anti-cancer agents. We plan to use an unusual sugar (an L-nucleoside) that is not normally found in the body. This unusual sugar has the property of being taken up by tumour cells but not normal cells. We will use this unusual sugar to transport a toxic compound inside tumour cells so that the tumour cells are killed. In this way, we will preferentially kill tumour cells but leave normal cells unaffected. Hence we will produce an anti-cancer agent that is ....The aim of this project to develop novel anti-cancer agents. We plan to use an unusual sugar (an L-nucleoside) that is not normally found in the body. This unusual sugar has the property of being taken up by tumour cells but not normal cells. We will use this unusual sugar to transport a toxic compound inside tumour cells so that the tumour cells are killed. In this way, we will preferentially kill tumour cells but leave normal cells unaffected. Hence we will produce an anti-cancer agent that is highly effective at killing tumour cells but has few side-effects because it does not enter normal cells. Experimentally we will synthesise compounds where the L-nucleoside is attached to a toxic agent, fluorouridine or cisplatin analogues. We will then assess the ability of these novel compounds to kill tumour cells grown in the laboratory as well as tumours growing in mice. Additionally we will attempt to determine the mechanism of action of these drugs by investigating the following: the transport properties of the drugs; how and where these drugs damage DNA; the effect of the gene, p53, which can act to stop tumour growth. The ultimate aim of this project is to develop a novel class of anti-tumour agent based on L-nucleosides. These L-nucleoside analogues are expected to be more efficient at killing tumour cells but have fewer side effects.Read moreRead less