HUMAN LARGE BOWEL CANCER AND CYTOCHROMES P-450

某些致癌素和抗癌剂对其活性的激活 细胞色素P-450依赖的混合酶催化细胞活性代谢产物 功能氧化酶系统。这项提案的目标是定义 该系统在人类大肠中的存在和功能； 确定参与细胞色素P-450的一种或多种特定形式 二甲基肼(器官特异性模型结肠癌致癌物)和 环磷酰胺(一种需要细胞色素P-450的抗癌剂 激活最近被证明在杀死人类结肠癌方面有效 培养中的细胞)；并确定调节细胞活性的因素 人结肠细胞色素P-450系统。追求这些目标将 人结肠细胞色素P-450存在形式的鉴定 和人类结肠肿瘤。我们将使用免疫化学鉴定 技术(例如，Western印迹)和标准纯化技术 定义P-450在人类大肠和结肠肿瘤中的作用。 使用抗体和其他抑制物和诱导剂将识别特定的 催化致癌物和/或化疗药物的活化。 通过这些方法，我们将检验细胞色素P-450系统 从而激活人体结肠中的致癌物和抗癌剂 在癌变和化疗中发挥作用。

The activation of certain caricnogens and anticancer agents to their cytoactive metabolites is catalyzed by the cytochrome P-450 dependent mixed function oxidase system. The goals of this proposal are to define the presence and functionality of this system in the human large bowel; to identify specific form or forms of cytochrome P-450 involved in the metabolism of dimethylhydrazine (organ-specific model colon carcinogen) and cyclophosphamide (an anticancer agent requiring cytochrome P-450 for activation recently shown to be effective in killing human colon tumor cells in culture); and to determine factors which regulate the activity of the cytochrome P-450 system in human colon. Pursuit of these goals will involve the identification of the forms of cytochrome P-450 in human colon and human colon tumors. We will employ both immunochemical identification techniques (e.g., Western blot) and standard purification techniques to define the P-450 constituency of the human large bowel and colonic tumors. Using antibodies and other inhibitor and inducers will identify specific forms catalyzing activation of carcinogens and/or chemotherapeutic agents. In these ways we will test the hypothesis that the cytochrome P-450 system activates carcinogens and anticancer agents in the human colon thereby playing a role in carcinogenesis and chemotherapy.