Repression Of Hepatic Drug Metabolism By Solid Tumours
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
The treatment of advanced cancer patients with drugs is difficult due to many confounding factors. The variability between patients in clearance rate has a significant impact on the success of chemotherapy. This is especially relevant to chemotherapeutic agents which have a narrow therapeutic range. Anti-tumour action will be lost if the drug is cleared too rapidly from the body, while high doses will lead to toxic side effects. A better understanding of the source of this variability will lead ....The treatment of advanced cancer patients with drugs is difficult due to many confounding factors. The variability between patients in clearance rate has a significant impact on the success of chemotherapy. This is especially relevant to chemotherapeutic agents which have a narrow therapeutic range. Anti-tumour action will be lost if the drug is cleared too rapidly from the body, while high doses will lead to toxic side effects. A better understanding of the source of this variability will lead to improvements in the manner in which chemotherapy is administered and would represent a welcome advance for cancer patients. The rate of breakdown of drugs in the body is largely determined by the levels of enzymes called cytochrome P450s (CYPs) in the liver. In humans CYP3A4 is responsible for the disposal of more than half of all drugs including several important chemotherapeutic agents. Clinical studies have found that the presence of an inflammatory response to tumours in tissues outside the liver reduces hepatic CYP3A4 activity. Factors released by immune as well as malignant cells within the tumour circulate via the bloodstream to the liver where they alter expression of many genes including CYPs. The study of the regulation of human genes is inherently difficult. It is nearly impossible to gain access to many body tissues in either healthy or sick individuals to examine co-ordinated gene function (or dysregulation). For this reason we made a transgenic mouse model of human CYP3A4 regulation which enables the human situation to be studied. In this project we will identify the tumour-derived factors which switch off the CYP3A4 transgene and analyse the signalling pathways within liver cells which mediate the response. A knowledge of this mechanism will permit the rational design of therapeutic strategies aimed at making chemotherapy safer and more effective. The availability of convenient animal models enables testing prior to clinical application.Read moreRead less
Novel Omega-3 Fatty Acid Epoxides And The Activation Of Cellular Survival Pathways
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have ....Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have potent protective effects that allow cells to survive in the presence of toxic stimuli. We have found that epoxides formed from the omega-3 fatty acid stearidonic acid are extremely potent protective agents in cells - more so that epoxides from omega-6 acids like arachidonic acid. The present project seeks to identify omega-3 fatty acid epoxides with potent and long-lived beneficial effects in cells, relate these properties to those of omega-6 fatty acid epoxides and then understand how the omega-3 epoxides enhance cell survival. The findings will provide a rational basis from which to understand the beneficial effects of dietary modification already seen in clinical studies. By understanding the biochemical and molecular events in cells that are activated by omega-3 fatty acid epoxides we may be able to design therapies, most likely involving changes in dietary fat intake, that could benefit individuals with arthritic, cardiovascular and other conditions. Given the high incidence of these conditions in this country the potential impact of the findings from this project could be highly significant and are consistent with the national research priority healthy ageing.Read moreRead less
Functional Interplay Of Transcriptional Activators In The Regulation Of The Cytoprotective Human CYP2J2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$480,828.00
Summary
Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have ....Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have been able to do this but we now know that the biologically important vitamin A derivative all-trans-retinoic acid (ATRA) can increase CYP2J2 in cells. In this project we will build on this novel finding to develop treatments that increase CYP2J2 in tissues. About 10% of people have a variant CYP2J2 gene that differs from the common form by one nucleotide. This polymorphic variant can decrease the amount of the CYP2J2 enzyme and increase cardiovascular risk. We ve found that this polymorphism is located in a critical control region of the gene and affects how the gene responds to transcription factors. The present project will study in detail the regulation of the CYP2J2 gene and its naturally occurring variant by transcription factors that bind to this control region. We will also test how the polymorphic version of the gene responds to stress stimuli and to treatments like ATRA that increase the amount of the wild-type gene in cells. Studying human gene regulation is difficult because we cannot easily measure their levels in individuals. So we will make transgenic mice to study human CYP2J2 regulation and will test whether the treatments we devise in cells also work in vivo. These studies will help us to design pharmacological strategies to increase CYP2J2 in cells. By maintaining the beneficial effects of CYP2J2, and understanding how these are altered in the variant, a significant outcome of the project could be a new treatment of cardiovascular disease.Read moreRead less
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