INTESTINAL TOXICITY OF 5-FLUOROURACIL AND LEUCOVORIN

5-氟尿嘧啶和亚叶酸的肠道毒性

• 批准号: 3185590
• 负责人: Jessie L.-S. Au
• 金额: $ 7.62万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1990-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3185590
• 关键词: 5 fluorouridine; cell growth regulation; cytotoxicity; drug adverse effect; drug metabolism; floxuridine; fluorouracil; folate; gastrointestinal epithelium; intestine disorder; leucovorin; neoplasm /cancer pharmacology; rectum neoplasms; thymidine; thymidylate synthase; uridine

This investigation is to examine the toxicity of 5-fluorouracil (FU) and leucovorin (LV) to intestinal epithelial cells. The antitumor activity of FU is due to the incorporation of its anabolite 5- fluorouridine triphosphate (FUTP) into fradulent RNA, and to its other anabolite 5-fluorodeoxyuridylate (FdUMP) which inhibits the synthesis of thymidylate and DNA by forming a ternary complex with the enzyme thymidylate synthase (TS) and the cofactor N-5, 10-methylenetetrahydrofolate (CH2-THF). In some tumor cells, folate analogues by increasing the intracellular CH2-THF concentration enhanced the TS inhibition and cytotoxicity of FU. Phase I-II trials of FU and LV showed that LV significantly improved the response rate of FU in gastric and colorectal cancers, but also potentiated its intestinal toxicity. Anticancer drugs cause intestinal toxicity by inhibiting the mitosis of the proliferating intestinal epithelial crypt cells. The crypt cell kill and recovery is determined by the concentration and duration of tissue exposure to the drug (AUC). The ongoing phase III trials use 10 vastly different regimens of FU and LV, which produce in the intestinal cells different drug AUC's and therefore likely different toxicity to patients. The objectives of this study are to examine the cellular metabolism, pharmacodynamics and mechanism of FU toxicity to the intestinal crypt cells, and the interaction between FU and folates. Preliminary studies, using our newly established cultured intestinal crypt (RIEC) cells derived from normal adult rats, showed that FU was incorporated into RNA, inhibited DNA synthesis and cell growth. The following studies will be done using the RIEC cells. 1. Define the relationship between the cytotoxicity and the AUC of FU alone and FU-folates, using the therapeutic/toxic AUC's from phase III FU-LV protocols. 2. Establish the mechanism of FU toxicity by examining its intracellular metabolism, DNA (inhibition of DNA synthesis) and RNA (incorporation into RNA) effcts, and the modulation of its activity by thymidine and uridine. 3. Compare the kinetics of TS inhibition with those of FdUMP and dUMP. 4. Assess the effects of folates. The proposed studies are expected to illustrate the pharmacology of FU and folates in the intestinal crypt cells, and the reversibility of drug toxicity by thymidine and/or uridine. The comparative cytotoxicity of different AUC's of FU-folates may indicate the relative intestinal toxicity of the different phase III FU-LV regimens.

本研究旨在检测5-氟尿嘧啶（FU）的毒性 和亚叶酸（LV）对肠上皮细胞的作用。 抗肿瘤 FU的活性是由于其合成代谢物5- 三磷酸氟尿苷（FUTP）转化成荧光RNA，并转化成其 其他合成代谢物5-氟脱氧尿苷酸（FdUMP），其抑制 通过形成三元复合物合成胸苷酸和DNA 用胸苷酸合成酶（TS）和辅因子N-5， 10-亚甲基四氢叶酸（CH 2-THF）。 在一些肿瘤细胞中， 叶酸类似物通过增加细胞内CH 2-THF 浓度增加FU的TS抑制作用和细胞毒性。 FU和LV的I-II期试验显示，LV显著 提高胃和结直肠FU的有效率 癌症，但也增强了其肠道毒性。 抗癌 药物通过抑制细胞的有丝分裂引起肠毒性， 肠上皮隐窝细胞增殖。 地穴细胞杀死 回收率取决于 组织暴露于药物（AUC）。 正在进行的III期试验 使用10种截然不同的FU和LV方案， 肠细胞不同的药物AUC，因此可能 对患者有不同的毒性。 本研究的目的是 检查细胞代谢、药效学和 FU对肠隐窝细胞的毒性机制，以及 FU和叶酸之间的相互作用。 初步研究，使用 我们新建立的培养肠隐窝（RIEC）细胞 来自正常成年大鼠，表明FU掺入 转化为RNA，抑制DNA合成和细胞生长。 以下 将使用RIEC细胞进行研究。 1.定义 细胞毒性与FU单药AUC之间的关系 和FU-叶酸，使用来自III期的治疗/毒性AUC FU-LV方案。 2.通过以下方式建立FU毒性机制： 检查其细胞内代谢，DNA（DNA抑制 合成）和RNA（掺入RNA）效应，以及 通过胸苷和尿苷调节其活性。 3.比较 TS抑制动力学与FdUMP和dUMP的动力学进行比较。 4. 评估叶酸的作用。 预计拟议的研究将 说明FU和叶酸在肠道中的药理学 腺窝细胞，以及胸苷对药物毒性的可逆性 和/或尿苷。 不同AUC的细胞毒性比较 FU-叶酸盐的相对肠毒性可能表明 不同的III期FU-LV方案。