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
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.
There is evidence that elderly cancer patients are often inappropriately treated because of their age. This is usually because of concerns that aged patients can not eliminate drugs as well as the young and, as a result, could end up being overdosed. Some drugs are removed from the body through the urine and adjusting for decreased kidney function (which often decreases with age) means that adequate doses can be calculated. However, many anti-cancer drugs are removed from the body by being broke ....There is evidence that elderly cancer patients are often inappropriately treated because of their age. This is usually because of concerns that aged patients can not eliminate drugs as well as the young and, as a result, could end up being overdosed. Some drugs are removed from the body through the urine and adjusting for decreased kidney function (which often decreases with age) means that adequate doses can be calculated. However, many anti-cancer drugs are removed from the body by being broken down (or metabolised) in the liver. The rate of this process is very difficult to estimate. Although many studies have shown that liver drug metabolism is decreased with age, it is unclear whether this is due strictly to age itself or some of the conditions which accompany ageing. We aim to study the removal of anti-cancer drugs in patients treated for cancer to see what the effects of ageing are. We will estimate the extent of liver breakdown and examine whether it is a function of age or rather of several factors which are often associated with age such as inflammation, reduced nutritional status and other medical conditions. The optimal outcome of the study will be methods for correctly adjusting the dose of anticancer drugs for maximal benefit to the elderly patient.Read moreRead less
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