Repression of hepatic drug metabolism by solid tumours

由于许多混杂因素，晚期癌症患者的药物治疗非常困难。患者间清除率的差异对化疗的成功有重要影响。这尤其与治疗范围较窄的化疗药物有关。如果药物从体内清除得太快，抗肿瘤作用就会丧失，而高剂量则会导致毒副作用。更好地了解这种可变性的来源将导致化疗方式的改进，这对癌症患者来说是一个可喜的进步。药物在体内的分解速度很大程度上取决于肝脏中细胞色素p450 （CYPs）的水平。在人类中，CYP3A4负责处理一半以上的药物，包括几种重要的化疗药物。临床研究发现，肝脏外组织中肿瘤的炎症反应会降低肝脏CYP3A4活性。肿瘤内的免疫细胞和恶性细胞释放的因子通过血液循环到肝脏，在那里它们改变了包括CYPs在内的许多基因的表达。对人类基因调控的研究本身就很困难。几乎不可能进入健康或患病个体的许多身体组织来检查协调的基因功能（或失调）。为此，我们制作了人类CYP3A4调控的转基因小鼠模型，使人类的情况得以研究。在这个项目中，我们将确定关闭CYP3A4转基因的肿瘤源性因子，并分析肝细胞内介导反应的信号通路。了解这一机制将允许合理设计旨在使化疗更安全、更有效的治疗策略。方便的动物模型的可用性使临床应用之前的测试成为可能。

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.