Repression of hepatic drug metabolism by solid tumours

由于多种混杂因素的影响，晚期癌症患者的药物治疗比较困难。患者之间清除率的差异对化疗的成功有很大的影响。这与治疗范围较窄的化疗药物尤其相关。如果药物从体内清除得太快，抗肿瘤作用就会丧失，而高剂量会导致毒副作用。更好地了解这种差异的来源将导致化疗方式的改善，并将代表着癌症患者可喜的进步。药物在体内的分解速度在很大程度上由肝脏中称为细胞色素P450(Cyps)的酶的水平决定。在人体内，细胞色素P3A4负责处置超过一半的药物，包括几种重要的化疗药物。临床研究发现，肝脏以外组织对肿瘤的炎症反应会降低肝脏细胞色素P3A4的活性。肿瘤内的免疫细胞和恶性细胞释放的因子通过血流循环到肝脏，在那里它们改变了包括细胞色素P450在内的许多基因的表达。研究人类基因的调控本身就很困难。无论是健康的人还是患病的人，几乎不可能获得许多身体组织来检查协调的基因功能(或失调)。为此，我们建立了人类细胞色素P3A4调控的转基因小鼠模型，为研究人体状况提供了可能。在这个项目中，我们将确定关闭CYP3A4转基因的肿瘤衍生因子，并分析肝细胞内介导这一反应的信号通路。对这一机制的了解将有助于合理设计旨在使化疗更安全和更有效的治疗策略。方便的动物模型的可用性使在临床应用之前进行测试成为可能。

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.