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I am a biochemist-pharmacologist determining how neurotransmitter transporters work, which will aid in the development in novel therapies for disorders of the nervous system
Potential Anti-tumour Agents: Iron Chelators Of The Pyridoxal Isonicotinoyl Hydrazone Class
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
Iron (Fe) is essential for proliferation. Generally, cancer cells have a high Fe requirement due to their rapid rate of proliferation making them very susceptible to iron chelators which deplete cells of Fe. The potential of this therapy has been confirmed by the entrance of the chelator, Triapine (Vion Pharmaceuticals), into clinical trials. Further, a wide variety of studies including clinical trials have shown that the clinically used Fe chelator, desferrioxamine (DFO), can have potent anti-t ....Iron (Fe) is essential for proliferation. Generally, cancer cells have a high Fe requirement due to their rapid rate of proliferation making them very susceptible to iron chelators which deplete cells of Fe. The potential of this therapy has been confirmed by the entrance of the chelator, Triapine (Vion Pharmaceuticals), into clinical trials. Further, a wide variety of studies including clinical trials have shown that the clinically used Fe chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial (Cancer Res 1990;50:4929), a marked decrease in tumour burden was observed while there was no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers serious problems, including that it requires long infusions and does not readily permeate cells. Considering this, during the current NHMRC grant, we developed a novel group of chelators that show far greater activity than DFO and Triapine at inhibiting cancer growth in vitro and in vivo (Richardson BLOOD 2004;104:1450). These studies have been published in high quality journals such as BLOOD and Clin Cancer Res (Richardson 1995, 1997, 1999, 2001, 2002, 2004a,b,c) Recently, a potent metastasis suppressor gene, known as differentiation related gene-1 (Drg-1), has been identified. Up-regulation of this molecule plays an important role in inhibiting the growth of primary cancers and their metastatic spread. Importantly, we have recently shown that our new chelators markedly up-regulate the expression of Drg-1 in cancer cells and at the same time markedly and selectively inhibit the growth of these cells (Richardson BLOOD 2004;104:2967). Our hypothesis is the marked increase in Drg-1 expression after treatment with chelators could inhibit cancer cell growth and metastasis. Studies in this NHMRC grant renewal will lead to the development of new therapies and a greater understanding of cancer metastasis and biology.Read moreRead less
Altered Hepatic Pharmacokinetics As A Consequence Of Drug- And Disease-induced Changes In Hepatic Vascularity.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the upt ....Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the uptake process. The diseases of most interest are liver cirrhosis, fatty liver disease, atherosclerosis and chronic heart failure, all of which together are leading causes of death in Western countries. They are also associated with liver dysfunction due to effects on liver vessels. We have a poor understanding of how the effects of these diseases and a number of drugs on liver vessels affect the functioning of the liver, especially in terms of how they affect drug breakdown or removal of drugs. This project seeks to understand these effects and proposes a number of animal studies as well as human studies to provide insight. The drugs to be studied are those most commonly used in patients with cardiovascular and liver diseases, as one of our main goals is to provide better therapeutic management in these patients.Read moreRead less
I am a pharmacologist-cell biologist-molecular biologist and chemist examining the metabolism of iron in normal and neoplastic cells and the development of iron chelators for the treatment of a variety of diseases e.g., ?-thalassaemia and cancer.
Expression And Regulation Of Human Genes Central To Drug Disposition In The Brain
Funder
National Health and Medical Research Council
Funding Amount
$339,375.00
Summary
The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). This is particularly true for the brain, where live human tissue is unavailable. For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. H ....The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). This is particularly true for the brain, where live human tissue is unavailable. For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. However, findings in animals often fail to meaningfully mirror what occurs in man. To progress our understanding of human genes in brain we need to develop models that more faithfully reproduce the human situation in an environment that is amenable to both manipulation and close examination, such as the novel 'humanized' mouse models described in this application. This application deals with the genes that control enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily and the drug transporter MDR1. These genes are present in several tissues including liver, gut, lung and brain. They form the main disposal pathway for foreign chemicals such as drugs, environmental pollutants and some cancer causing chemicals. In addition they are involved in the breakdown of several important internally produced substances, such as steroid hormones. We postulate that altered formation of CYP3A enzymes and MDR1 in brain can have a dramatic impact on the action of many important drugs and may affect the way the brain responds in a behavioral sense to hormones, such as sex steroids. In addition, this work will provide a new and useful information relevant to the design and development of the plethora of drugs that act on the central nervous system.Read moreRead less