Clozapine Toxicity: Role Of Pharmacogenetic Variation In CYP Enzymes And Bioactivation Mechanisms In Patient Neutrophils
Funder
National Health and Medical Research Council
Funding Amount
$336,000.00
Summary
The treatment of mental disorders such as schizophrenia involves the administration of potent drug combinations to patients. Some individuals, however, do not respond to commonly-used antipsychotic drugs and their condition only improves with a unique drug called clozapine. The major problem with clozapine is its toxicity toward blood cells, heart and other organs. All people who receive clozapine must be monitored closely, especially in the first 3-4 months after starting therapy. Several new d ....The treatment of mental disorders such as schizophrenia involves the administration of potent drug combinations to patients. Some individuals, however, do not respond to commonly-used antipsychotic drugs and their condition only improves with a unique drug called clozapine. The major problem with clozapine is its toxicity toward blood cells, heart and other organs. All people who receive clozapine must be monitored closely, especially in the first 3-4 months after starting therapy. Several new drugs have been suggested to be safer versions of clozapine but these are all ineffective. Clozapine is the only agent that is effective in people who do not respond to the other drugs used to treat schizophrenia. Thus, clozapine toxicity, which necessitates discontinuation of the drug, is a devastating outcome because there is no alternative treatment that is available. Another significant problem with clozapine is that its rate of removal from the body is slowed down by many other drugs that are used concurrently. The problems with clozapine occur in some but not all individuals. This suggests that the patient's genetic makeup and their exposure to drugs and environmental agents determine the incidence of toxicity. The present project looks at how clozapine is removed from the body and how it is converted into a toxic product that damages cells. These processes will be examined, with emphasis on differences between individual patients, and strategies to protect cells from damage from the toxic derivative will be tested. Corresponding studies will be done in patients who are receiving clozapine as treatment for psychoses. We will be able to compare experimental and clinical findings in order to identify those patients who appear to be at risk. This will be possible before the toxic effects occur and will help us to identify subjects in whom the drug should only be used with great care. We may also devise strategies that will minimise the incidence of toxicity.Read moreRead less
Human Arylamine N-acetyltransferase Regulation And Function - Effect Of Genetic Poymorphisms.
Funder
National Health and Medical Research Council
Funding Amount
$421,980.00
Summary
How we handle chemicals that enter our bodies depends on a series of enzymes that are responsible for breaking down the chemicals and eliminating them. The activity of many of these enzymes varies between individuals so our responses to chemicals and drugs is different for each individual. Some of the enzymes vary because of inherited mutations, but others vary because of the diets we eat and the environment in which we live. This project will investigate a major enzyme called acetlytransferase ....How we handle chemicals that enter our bodies depends on a series of enzymes that are responsible for breaking down the chemicals and eliminating them. The activity of many of these enzymes varies between individuals so our responses to chemicals and drugs is different for each individual. Some of the enzymes vary because of inherited mutations, but others vary because of the diets we eat and the environment in which we live. This project will investigate a major enzyme called acetlytransferase that has been implicated as a risk factor in diseases such as cancer, asthma, liver cirrhossis and adverse drug reactions. We plan to look at the enzyme in cells and determine what environmental factors contribute to its variation between individuals, and how this impacts on the genetic mutations that have been found in its gene. From these studies, we will have a much better undersanding of how different people metabolise foreign chemicals, and should be able to predict those most at risk of certain diseases.Read moreRead less
Glycine Transporters regulate the concentration of glycine in the spinal cord and brain. It has been suggested that elevating glycine levels in these regions may be useful in treating pain and schizophrenia. This project will provide the basis for the development of new glycine transport inhibitors that may be used to treat these conditions.
Pharmacological Targeting Of Arylamine N-Acetyltransferase I
Funder
National Health and Medical Research Council
Funding Amount
$474,653.00
Summary
This project will investigate a novel approach to controlling how cancer cells grow and spread. It plans to study whether a protein termed N-acetyltransferase is a key to determining whether cancer cells can change thier characteristics, allowing them to invade other tissues. In addition, novel approaches to target this protein are proposed. If successful, the work outlined in this project will open new avenues to understanding and trerating cancers.
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 wide variety of diseases eg., ?-thalassaemia, cancer and Frie
Cytochrome P450 CYP3A Regulation In Humanized Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$376,980.00
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). 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. ....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). 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 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 'humanised' mouse models described in this application. This application deals with the regulation genes that control liver enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily. These enzymes are present in several tissues including liver, gut, lung and breast. 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. Altered formation of CYP3A enzymes can have a dramatic impact on the action of many important drugs and may predispose to some forms of cancer. In this project, we will insert the genes for all four human CYP3A enzymes into mice. We expect that these 'humanised' mouse models will effectively enable the human situation to be studied in a convenient animal model and allow detailed studies to be performed. A knowledge of the mechanisms involved in CYP3A enzyme formation is of particular importance to the fields of drug and steroid metabolism (both in health and in disease states), liver diseases and foetal pharmacology. In addition, these models will provide a new and useful tool for drug development.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
Molecular Mechanisms Of Human Cytochrome P450 CYP3A4 Gene Regulation
Funder
National Health and Medical Research Council
Funding Amount
$196,059.00
Summary
Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. Cytochrome P450 3A4 (CYP3A4) is arguably the single most important factor is how humans handle therapeutic drugs. It has been estimated that over 60% of all ....Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. Cytochrome P450 3A4 (CYP3A4) is arguably the single most important factor is how humans handle therapeutic drugs. It has been estimated that over 60% of all drugs presently on the market are broken down, either in full or in part, by this enzyme. The amounts of CYP3A4 expressed in the liver differs markedly between individuals, and explains a great deal of the large variation in the way people break down drugs. Also, variations in the levels of CYP3A4 in the liver may be an important factor in both prostate cancer (the most common cancer in men) and the risk of developing leukemia after receiving chemotherapy for other cancers. The present projects builds on discoveries concerning the regulation of cytochrome P450 enzymes made by our group over the last few years, including an in-depth understanding of the way the production of CYP3A4 is increased by some drugs. In this project we seek to understand why individuals differ so much in terms of the amount of CYP3A4 in the liver (up to 10-fold) and why this enzyme is predominantly expressed in the liver and to as lesser extent, the intestine, while not being found at all in many other tissues. An understanding of these issues will allow us to: Y predict how patients will respond to drugs (pharmacogenetic testing). Y determine susceptibility to certain diseases (e.g., prostate cancer). Y develop novel drugs that can influence CYP3A4 production in the liverRead moreRead less
Development Of DNA Phosphate Crosslinking Agents As Potential Anticancer Drugs
Funder
National Health and Medical Research Council
Funding Amount
$392,545.00
Summary
The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar ....The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leukaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. Alkylating agents are one of the most important classes of anticancer drug. They bind irreversibly to the bases in DNA and weld the two strands of the double helix together. This cross-link is a powerful block to DNA replication and leads to the death of cancer cells by the process of programmed cell death. Cancer cells generally become resistant to alkylating agents by invoking repair mechanisms that remove the drug from the DNA bases, a response which breaks the cross-link and returns the DNA to its normal state. In this project, we are developing a new type of alkylating agent that reacts not with the DNA bases but with the phosphate groups of the DNA backbone. By this means the strands of DNA can again be cross-linked but now the linkage is between parts of the DNA that cancer cells cannot separate. In this way, we hope to be able to devise new drugs that are resistant to the normal mechanisms of DNA repair so that they will be active against drug-resistant tumours.Read moreRead less