The Evaluation Of Gamma-glutamylcyclotransferase As A Novel Target For Cancer Therapy And Diagnosis
Funder
National Health and Medical Research Council
Funding Amount
$433,900.00
Summary
Gamma glutamylcyclotransferase (GGCT) plays a pivotal role in regulating the synthesis of glutathione, a compound that is essential for life and regulates many intracellular processes. Several recent studies have shown that GGCT is highly expressed in cancer cells . This study will determine if GGCT is a target for cancer chemotherapy or if it can be used for cancer diagnosis. This study may also provide a new treatment for patients with glutathione synthetase deficiency.
Glutathione Transferase Deficient Mice To Probe For Adverse Drug Reactions
Funder
National Health and Medical Research Council
Funding Amount
$562,933.00
Summary
A family of enzymes called glutathione transferases (GST) that metabolize foreign chemicals and therapeutic drugs have been shown to be a significant cause of drug resistance in cancer chemotherapy. It has been suggested that inhibitors of GSTs could be used in cancer treatment to counter drug resistance or to slow the metabolism and enhance the activity of some drugs. Some GSTs carryout important enzymatic reactions with endogenous substrates and others have important non-enzymatic functions su ....A family of enzymes called glutathione transferases (GST) that metabolize foreign chemicals and therapeutic drugs have been shown to be a significant cause of drug resistance in cancer chemotherapy. It has been suggested that inhibitors of GSTs could be used in cancer treatment to counter drug resistance or to slow the metabolism and enhance the activity of some drugs. Some GSTs carryout important enzymatic reactions with endogenous substrates and others have important non-enzymatic functions such as the regulation of signaling pathways within cells and the modulation of calcium ion channels that are involved in muscle contractions. The generic inhibition of all GSTs could therefore have significant adverse physiological effects. We propose to make mice deficient in specific GSTs and to study their physiological responses. The results of these studies will indicate which GSTs can be safely inhibited without the risk of deleterious side effects. These studies are important because adverse reactions to therapeutic drugs are a significant cause of hospital admissions and death.Read moreRead less
Structure And Gene Regulation Of Human Glutathione Transferase GSTT1-1
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Glutathione transferases (GSTs) play a critical role cellular detoxification system. They belong to the phase II enzymes of the xenobiotic metabolism and conjugate a wide range of drugs and chemicals with glutathione to increase water solubility and thereby enhancing their elimination. The conjugation with glutathione is considered an important detoxification route for most chemicals. However, it has been shown that in many cases this pathway leads to metabolites that are more toxic than the ini ....Glutathione transferases (GSTs) play a critical role cellular detoxification system. They belong to the phase II enzymes of the xenobiotic metabolism and conjugate a wide range of drugs and chemicals with glutathione to increase water solubility and thereby enhancing their elimination. The conjugation with glutathione is considered an important detoxification route for most chemicals. However, it has been shown that in many cases this pathway leads to metabolites that are more toxic than the initial chemical or drug. The gene deletion of the particular human GSTT1 gene results in total loss of this particular enzyme activity in all tissues of homozygous null genotype individuals. This phenotype is called non-conjugator . Non-conjugators seem to have a higher risk to develop certain cancer types, e.g. urinary bladder cancer or brain tumours, while they seem to be less susceptible for others, e.g. liver. Occupational exposure to chemicals is of relevance in such relationships because the GSTT1 enzyme metabolises a wide range of industrial chemicals including solvents but also monomers used in the production of rubbers and other polymers. In addition, GSTT1 seems to influence the efficay of cancer chemotherapy by inactivating certain anti-cancer drugs, eg. BCNU, that is predominantly use in treatment of brain tumours. The aims of this study include the characterisation of the tissue-specific activity and the influence of xenobiotics on the protein levels of this enzyme. The study leads to a better understanding of the etiology of exposure related cancers and of the mechanisms of resistance to cancer chemotherapy. Such knowledge allows the development of concepts for the optimisation of efficacy and minimisation of side effects in chemotherapy.Read moreRead less
The Role Of Zeta And Omega Class Glutathione Transferases In Endobitic And Xenobiotc Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$481,980.00
Summary
The glutathione transferases are enzymes that play a significant role in the protection of cells from harmful chemicals in the environment. While some of the chemicals that are detoxified by glutathione transferases cause cancer, and other diseases, these enzymes also eliminate some of the drugs that are used in chemotherapy. Variations in the type and amount of glutathione transferase in a cell can make a normal cell susceptible to cancer causing chemicals and make a cancer cell resistant to an ....The glutathione transferases are enzymes that play a significant role in the protection of cells from harmful chemicals in the environment. While some of the chemicals that are detoxified by glutathione transferases cause cancer, and other diseases, these enzymes also eliminate some of the drugs that are used in chemotherapy. Variations in the type and amount of glutathione transferase in a cell can make a normal cell susceptible to cancer causing chemicals and make a cancer cell resistant to anti cancer drugs. We have discovered two new forms of glutathione transferase called Zeta and Omega. The new research to be undertaken here is aimed at understanding the role of these new enzymes in protection against foreign chemicals and the role these enzymes play in normal cellular metabolism. Because the Zeta class glutathione transferase is part of a pathway designed to eliminate excessive amounts of the amino acid tyrosine, we will determine if its inhibition will provide a new treatment for patients with a disease called hereditary tyrosinemia. We will also study the genetic and environmental factors that determine the amount of Zeta and Omega glutathione transferase produced in cellsRead moreRead less
Pharmacogenetic And Structural Investigation Of The Omega Class Glutathione Transferases
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. The Omega class of glutathione transferases are important because they are involved in the metabolism of arsenic and because t ....Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. The Omega class of glutathione transferases are important because they are involved in the metabolism of arsenic and because they have been shown to influence the age-at-onset of both Alzheimer s and Parkinson s diseases. The present studies will investigate the structure and function of different Omega class glutathione transferases and determine how they interact with arsenic based drugs. These studies will attempt to determine why the toxicity of arsenic varies between individuals and aims to prevent adverse reactions to arsenic containing drugs used in cancer therapy. These studies will also investigate the mechanism by which the inheritance of certain forms of Omega class glutathione transferase can affect the age at-onset of Alzheimer s disease and Parkinson s disease. The understanding of this mechanism may provide the basis for a therapy that could delay or prevent the onset of these common diseases.Read moreRead less
Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, ....Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, particularly in cells from the brain. Our recent studies indicate that this mitochondrial pool of glutathione is particularly important in limiting the death of cells from the brain when exposed to damaging substances that are increased in some diseases. Thus, the capacity of mitochondrial glutathione to deal with such substances might be a factor in determining the extent of cell loss in the brain, which is an important determinant of symptoms in some of the major neurological diseases. Consistent with this possibility, we have obtained evidence indicating that decreases in glutathione in the mitochondria contribute to the cell death and brain damage that results from a stroke. In our proposed studies, we will investigate the function of mitochondrial glutathione in the two major cell populations from the brain, neurons and astrocytes. We will characterise the protective role of the glutathione and investigate how it enters the mitochondria and what factors influence the amount that is present. This will provide new insights into the function of glutathione in the mitochondria and could also suggest novel approaches for manipulating this antioxidant pool. We will also study models of stroke and some related brain disorders to more directly test the role of this antioxidant in disease and to assess whether manipulating the content of glutathione in the mitochondria has the potential to reduce damage and improve function in these disordersRead moreRead less
The Role Of Glutathione Transferase P1 In Regulating Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$436,882.00
Summary
Recent studies have shown that a single amino acid change in an enzyme called glutathione tranferase Pi (GSTP)1 protects against the likelihood of developing asthma. This enzyme is found in the cells that line the airways and detoxifies harmful chemicals such as those found in pollutants and cigarette smoke. The aim of our study is to understand how GSTP1 protects against the development of asthma.