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
Astrocytic Glutamate Transporters: Molecular Characteristics Of Their Activity-dependent Localization And Targeting
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
Dysfunction of glutamate transport is implicated in the pathology of neurodegenerative conditions. Our aim is to understand how the molecules responsible for glutamate transport are organized on the cell surface and how their movement within cells regulates transporter activity. Advances of this type will indicate new pharmacological and molecular biological strategies for the management of brain disorders.
Arachidonic Acid Modulation Of Glutamate Transporters
Funder
National Health and Medical Research Council
Funding Amount
$286,980.00
Summary
Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also fo ....Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also for long term neurological disorders such as Alzheimer's disease. In this project we shall investigate a novel mechanism for regulating the activity of glutamate transporters and explore the possibility of pharmacologically manipulating glutamate transporters. This work may lead to the development of novel compounds that improve transporter function and reduce the pathological consequences of impaired transporter function. Such compounds may have therapeutic potential as neuroprotectants in the treatment of neurological disorders such ischaemic brain damage or neurodegenerative disorders such Alzheimer's disease.Read moreRead less
Metabotropic Glutamate Receptors: Pharmacological Studies Of Receptor Subtypes In Neuronal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$145,770.00
Summary
Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexp ....Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexplored and is the topic under investigation in this project. How their activation affects cellular signaling switch on will be investigated to gain an understanding of the roles metabotropic glutamate receptors play in acute brain injury (eg stroke) and chronic neurodegenerative conditions (eg Huntington's chorea and Alzheimer's disease).Read moreRead less