IN VITRO TEST OF INTESTINAL TOXICITY OF ANTICANCER DRUGS

抗癌药物肠道毒性的体外试验

• 批准号: 3491682
• 负责人: M GUILLAUME WIENTJES
• 金额: $ 5万
• 依托单位: TRINI LABORATORIES
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-20 至 1988-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3491682
• 关键词: DNA; alkylating agents; antimetabolites; antineoplastics; cytotoxicity; drug adverse effect; fluorouracil; gastrointestinal toxin absorption; methotrexate

Intestinal toxicity is a major side effect of cancer chemotherapy. The procedures to isolate and cuture rat small intestinal epithelial crypt cells, which are the target cells for drug toxicity, have recently been developed. The overall objectives of this study is to establish an in vitro method to quantify the in vivo intestinal toxicity of anticancer drugs. The phase I study is to examine the feasibility of using an in vitro toxicity assay to predict the intestinal toxicity of anticancer drugs using the rat as an animal model. The research plan is to evaluate and correlate the druginduced rat intestinal crypt cell toxicity in vitro and the intestinal disturbances in intact animals. Two antimetabolites, 5fluorouracil and methotrexate, are selected as the test drugs. Drug toxicity is determined by the concentration as well as the duration of exposure to the drug. In order to make valid comparison of the in vitro and in vivo toxicities, the in vitro and in vivo studies will be done under similar drug concentrationtime (AUC) profiles. The crypt cytotoxicity and the intestinal disturbances, observed under the same AUC of the drug, will be compared and a qualitative and quantitative correlation will be sought. The phase II study will examine the general applicability of the in vitro assay using at least three drugs from each of the major drug classes including antimetabolites, alkylators and DNA reacting agents, and compare the rat and human cells. Comparison of the cytotoxic responses of rat and human crypt cells is necessary to understand the applicability and limitation of the crypt cytotoxicity assay to predict for drug toxicity in patients.

肠道毒性是癌症化疗的主要副作用。 大鼠小肠上皮细胞的分离培养 作为药物毒性靶细胞的隐窝细胞， 最近开发的。 本研究的总体目标是 建立体外定量方法， 抗癌药物的毒性。 第一阶段研究是审查 使用体外毒性测定来预测 使用大鼠作为动物的抗癌药物的肠毒性 模型 研究计划是评估和关联 药物诱导的大鼠肠腺细胞毒性及 完整动物的肠道紊乱。 两种抗代谢药， 5氟尿嘧啶和甲氨蝶呤作为试验药物。 药物毒性是由浓度以及 暴露于药物的持续时间。 为了使 比较体外和体内毒性、体外和 将在相似的药物浓度时间下进行体内研究 (AUC)数据区. 隐窝细胞毒性和肠 在药物的相同AUC下观察到的干扰， 比较和定性和定量的相关性将是 寻找。 第二阶段的研究将审查 在体外试验中，使用来自每种药物的至少三种药物， 主要药物类别，包括抗代谢药、烷化剂和DNA 反应剂，并比较大鼠和人类细胞。 大鼠和人隐窝细胞毒反应的比较 细胞是必要的，以了解适用性和局限性， 细胞毒性试验预测药物毒性 患者