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
Interaction Of New Kinase Inhibitor Drugs With Multi-drug Resistance (MDR) Transporter Proteins.
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, ....Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, multidrug transporters sometimes interfere with drug therapy. They can prevent efficient absorption of drugs, increase the rate of drug elimination from the body, or prevent drug access to some tissues . Moreover, the activity of the transporters is quite variable, both between patients and within the same patient over time. This makes it difficult to provide optimal drug doses, particularly when treating cancer, where the drugs must be given at the maximum tolerated dose. The presence of drug transporter proteins in tumour cells can prevent entry of anticancer drugs, rendering them resistant to treatment. This is the main cause of failure in chemotherapy. This project will investigate a class of very promising new anticancer drugs, kinase inhibitors, to determine whether they are pumped by multidrug transporters, whether they alter the amounts of drug transporters in cells, and whether they alter transporter activity. We will also determine the consequences that follow from this for drug therapy. This information will help clinicians to rationally optimise therapy with the new drugs, to identify in advance both favourable (synergistic) and unfavourable (harmful) drug interactions in combination chemotherapy, to optimise drug doses and to minimise toxic side effects. The information will also add to our general understanding of drug absorption and elimination, and to the basic science of the remarkable multidrug transporter proteins.Read moreRead less
One of the hallmarks of cancer cells is their ability to divide and multiply in an uncontrolled manner. Specific proteins that make up the skeleton of cells (cytoskeleton) play an important part in the cell division process and as such make extremely important targets for anticancer therapy. Our research is developing ways to best target cell division proteins so that we can make drug resistant cancer cells sensitive to chemotherapy.
Characterisation Of The Anti-apoptotic Function Of P-glycoprotein And Transcriptional Regulation Of The MDR1 Gene.
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a protein called P-glycoprotein (P-gp) that extrudes cytotoxic drugs out of the cancer cell. We have defined a novel role for P-gp in protecting cells against death induced by non-drug stimuli, where an efflux effect of P-gp would have no obvious benefit. This broader survival effec ....The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a protein called P-glycoprotein (P-gp) that extrudes cytotoxic drugs out of the cancer cell. We have defined a novel role for P-gp in protecting cells against death induced by non-drug stimuli, where an efflux effect of P-gp would have no obvious benefit. This broader survival effect of P-gp may be explained by its ability to regulate the activity of key enzymes (caspases) that exist within cells to induce cell suicide when appropriate. Many chemotherapeutic drugs activate caspases to kill target cells and as P-gp can inhibit caspase activation, it is therefore possible that P-gp affects the activity of anti-cancer drugs by both removing the drugs from the target cells and inhibiting the pathways through which the drugs can kill a cell. We have mutated P-gp to define the region that is necessary for its caspase regulatory function. We are now identifying the proteins that bind to this region so that we can determine how P-gp regulates caspase activation. In addition, we have defined the manner by which P-gp expression is kept low in normal cells and is upregulated following exposure of cells to chemotherapeutic drugs. The gene encoding P-gp (MDR1) is normally switched off due to the way it is packaged within a nuclear structure called chromatin. We have shown that treatment of cancer cell lines with chemotherapeutic drugs alters chromatin in such a way that the MDR1 gene is activated. We will identify the proteins and complexes involved in drug-mediated regulation of chromatin structure and determine if this phenomenon occurs within patients receiving chemotherapy. Our new findings may lead to novel treatment options for patients that have MDR cancers and may provide insight into possible new ways to inhibit the formation of P-gp-expressing MDR tumors.Read moreRead less
Improving The Use Of Chemotherapy By Targeting The Inflammatory Response
Funder
National Health and Medical Research Council
Funding Amount
$570,876.00
Summary
Patient differences in clearance of anti-cancer drugs have a major impact on the success of chemotherapy. Benefit is lost if the drug is cleared too rapidly, while slow elimination causes toxicity. We will use well characterised mouse models that mirror the human situation to study the causes and effects of reduced drug metabolism in cancer. The data will guide future human studies that will result in improved diagnostic and therapeutic interventions to improve the tolerance of chemotherapy.
I am a cancer cell biologist investigating molecular mechanisms of leukaemia cell resistance to chemotherapeutic drugs, and novel strategies for the management of high risk or relapsed disease. For these purposes I have developed orthotopic xenograft mode
Investigation Of A Tumour Enzyme As A Predictor Of Patient Response To An Australian Anti-cancer Drug
Funder
National Health and Medical Research Council
Funding Amount
$362,082.00
Summary
GSAO is a new cancer drug we have developed that is currently being trialed in cancer patients. Our investigation of how GSAO works has revealed that it needs to be activated by an enzyme expressed by certain types of cancers. This finding implies that GSAO should be more effective against cancers that make this enzyme. Our aim is to establish this concept in laboratory based experiments as a basis for selection of patients who are more likely to benefit from GSAO treatment.
Development Of Small Molecules For The Treament Of Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$684,379.00
Summary
Colon cancer remains one of the leading causes of cancer related deaths in Australia and in the developed world. Despite improvements in prevention and therapies, there remains a considerable need for efficacious therapeutic options. We have identified a lead compound inhibiting the growth of cancer cells. We will progress this series further toward clinical trials and aim to provide patients with a new orally available molecule with potent activity against colon cancer.
The Role Of Intracellular Uptake And Retention Of Abl Kinase Inhibitors In Modifying Clinical Response In CML
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Imatinib is one of the first targeted anticancer drugs to be clinically developed. It is designed to inhibit the kinase activity of BCR-ABL, a mutant protein found in some cases of leukaemia, particularly chronic myeloid leukaemia. Blocking the kinase activity of BCR-ABL has proven to be highly effective therapy for most patients, achieving prolonged remissions and significantly improving survival. However resistance to imatinib is a problem, including failure to respond to imatinib, loss of res ....Imatinib is one of the first targeted anticancer drugs to be clinically developed. It is designed to inhibit the kinase activity of BCR-ABL, a mutant protein found in some cases of leukaemia, particularly chronic myeloid leukaemia. Blocking the kinase activity of BCR-ABL has proven to be highly effective therapy for most patients, achieving prolonged remissions and significantly improving survival. However resistance to imatinib is a problem, including failure to respond to imatinib, loss of response, and long term persistence of low levels of leukaemia. New ABL kinase inhibitors (AKIs) have been developed that are more potent than imatinib, but they also appear to be prone to resistance. One potentially important cause of resistance to AKIs is the ability of some leukaemic cells to modify their cellular pathways to reduce the effective concentration of the drug by either reducing its movement into the cell (influx) or increasing its movement out (efflux). We will investigate the mechanisms used by resistant leukaemic cells to reduce intracellular drug levels of these AKIs and test ways of countering these effects by blocking the proteins responsible for drug efflux or promoting drug influx. These studies will use our stored collections of leukaemic cells from responsive and resistant patients to determine the importance of specific influx and efflux pumps. It will help to identify patients where this form of resistance is limiting response. This may allow us to develop more effective AKIs that are less prone to these forms of drug resistance. We will also test whether other anti-cancer drugs have an impact on AKI drug transport because this could reduce the effectiveness of combination treatment. The effects on drug transport of concomitant administration of commonly used drugs together with AKIs will also be studied because this can reduce the effectiveness of AKis or in some cases improve their effectiveness by increasing their uptake and retention.Read moreRead less
Molecular And Cellular Determinants Of Tubulin-targeted Drug Action
Funder
National Health and Medical Research Council
Funding Amount
$484,500.00
Summary
Cancer is the leading cause of death in developed countries. Despite advances in the use of combination chemotherapy, drug resistance is the major cause of treatment failure. An important component in the treatment of many childhood and adult cancers are the antimicrotubule agents. These drugs target an important part of the cell skeleton called the tubulin-microtubule system that is responsible for many important events including cell division. It is the ability of these drugs to disrupt cell d ....Cancer is the leading cause of death in developed countries. Despite advances in the use of combination chemotherapy, drug resistance is the major cause of treatment failure. An important component in the treatment of many childhood and adult cancers are the antimicrotubule agents. These drugs target an important part of the cell skeleton called the tubulin-microtubule system that is responsible for many important events including cell division. It is the ability of these drugs to disrupt cell division in cancer cells that makes them so effective and such important targets for new drug design. Unfortunately, the reasons why tumours develop resistance to these drugs or even why some tumours do respond well is not understood. This proposal will determine how the makeup and stability of the tubulin-microtubule proteins influences how these drugs work in both childhood and adult tumour cells. Finally, components of drug resistant tumour cells will be examined using technology that allows us to simultaneously separate and identify hundreds of proteins some of which may provide useful targets for the design of new drugs for the treatment of cancer. To improve cancer survival rates it is essential to accurately target the use of existing drugs and to identify new targets for anticancer drug development.Read moreRead less